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Anticancer Activity of Glycoside Amides: A Comprehensive Review

Executive Summary

Glycoside amides represent a compelling class of compounds with significant potential in oncology. These

molecules, characterized by a saccharide unit linked to an amide moiety, are distinct from traditional glycosides

and offer unique chemical and biological properties. Research indicates their multifaceted anticancer

mechanisms, including the induction of apoptosis and cell cycle arrest, direct interaction with critical cellular

pathways and molecular targets, and the exploitation of cancer-specific metabolic vulnerabilities through

sophisticated prodrug strategies. Preclinical studies have demonstrated their efficacy and selectivity across

various cancer types, encompassing both natural derivatives like amygdalin and cardiac glycosides, as well as an

expanding array of synthetic compounds. While challenges in synthesis, pharmacokinetics, and clinical

translation persist, ongoing advancements in chemical synthesis, targeted drug delivery, and computational

modeling are paving the way for their optimized development. The strategic design of glycoside amides to

leverage the unique biological landscape of cancer cells positions them as promising candidates for future

precision oncology, offering the potential to enhance therapeutic efficacy while minimizing systemic toxicity.

1. Introduction to Glycoside Amides in Cancer Therapy

The field of oncology continuously seeks novel therapeutic agents that can effectively target cancer cells while

sparing healthy tissues. Glycoside amides, a specialized group of glycomimetics, have emerged as promising

candidates due to their unique structural features and diverse biological activities. This report delves into their

definition, chemical characteristics, and their evolving role in medicinal chemistry, particularly in the context of

cancer treatment.

1.1. Definition, Chemical Structure, and Classification of Glycoside Amides

Glycosides broadly encompass biologically active compounds where a sugar group (glycone) is covalently linked

to a non-sugar group (aglycone).

While the most common linkage is an O-glycosidic bond, these connections

can also involve other atoms such as sulfur (forming S-glycosides or thioglycosides), nitrogen (forming N-

glycosides or glycosylamines), or even carbon (C-glycosides, though this term is generally discouraged by

IUPAC).

Amides, distinct from glycosides, are organic compounds defined by a carbonyl group directly attached to a

nitrogen atom (R-CO-NR'R'').

A notable characteristic of the amide functional group is the partial double-bond

character of its C-N bond, which imposes restricted rotation and influences the molecule's three-dimensional

conformation.

N-glycosyl amides, the primary focus herein, represent a specific class of glycomimetics where the typical oxygen

atom in a glycosidic linkage is replaced by a nitrogen atom, resulting in the formation of an amide bond with the

saccharide moiety.

In biological systems, the process of N-linked glycosylation involves the attachment of an

oligosaccharide, a complex carbohydrate, to the amide nitrogen of an asparagine (Asn) residue within a protein.

This forms a β-linkage where the anomeric carbon of the sugar is directly joined to the amide nitrogen.

The precise chemical nature of the glycosidic linkage, particularly the unique conformational constraints imposed

by the partial double-bond character of the amide bond in N-glycosyl amides, is not merely a chemical detail.

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These structural rigidities are fundamental determinants of how these molecules interact with biological targets.

The specific three-dimensional shape and flexibility of a drug candidate are crucial for its ability to bind

effectively to enzymes, receptors, or other cellular components. Thus, the inherent structural rigidity of N-

glycosyl amides can lead to higher specificity and potency in their biological actions. However, achieving this

precise three-dimensional structure demands sophisticated synthetic strategies.

The synthesis of N-glycosyl amides often presents considerable challenges, including low yields, susceptibility

to hydrolysis, and a loss of stereocontrol through anomerization processes when glycosyl amines are used as

direct precursors.

Furthermore, traditional methods may necessitate the use of hazardous and potentially

explosive reagents.

To overcome these synthetic hurdles, sequential synthesis is a proposed strategy, employing

glycosyl azides as intermediates, followed by their reduction and immediate derivatization with activated

carboxylic acids.

Additionally, radical-based approaches are emerging as transformative alternatives for N-

glycosylation, offering new avenues for efficient and selective synthesis.

These persistent difficulties in N-

glycosyl amide synthesis represent a significant barrier to their widespread drug development and clinical

translation. Regardless of a compound's biological promise, if it is difficult and expensive to synthesize at the

required scale and purity, its progression through preclinical and clinical trials is severely hampered. Therefore,

innovations in synthetic methodology, such as sequential synthesis from glycosyl azides and radical-based

approaches, are not just academic advancements but direct enablers for producing these compounds at the scale

and purity required for pharmaceutical applications, thereby unlocking their full therapeutic potential.

1.2. General Biological Significance and Role in Medicinal Chemistry

Glycosides are broadly recognized for their diverse biological activities, with the glycosidic residue frequently

playing a pivotal role either in directly eliciting a therapeutic effect or in enhancing pharmacokinetic parameters

such as solubility, cellular transport, and bioavailability.

This dual functionality highlights a strategic

consideration in drug development for glycoside amides: some may be designed to directly engage biological

targets via their sugar moiety, while others may primarily utilize glycosylation to improve drug-like

characteristics (e.g., increased solubility, enhanced stability against enzymatic degradation)

, thereby improving

the delivery of an active non-sugar component.

N-glycosyl amides, and more broadly N-glycopeptides, are integral to numerous essential cellular recognition

processes, including inflammation, immune response, tumor proliferation, and metastasis.

N-glycosylation of

peptides and proteins stands as one of the most complex and abundant types of co-translational modifications

observed in nature.

As glycomimetics, N-glycosyl amides are specifically designed to mimic carbohydrates and

frequently exhibit enhanced stability against enzymatic degradation, a highly valuable property for drug

candidates as it can prolong their presence and activity in the body.

They have been investigated as enzyme

inhibitors, demonstrating the capacity to regulate the activity of glycosidases or glycosyltransferases, and have

shown potential in modulating glycogen phosphorylase activity, which is relevant for conditions such as type 2

diabetes.

A critical observation in cancer biology is that changes in glycosylation patterns are a significant hallmark of

cancer, associated with various pathological activities, and serve as crucial biomarkers and therapeutic targets for

cancer diagnosis and treatment.

Aberrant glycosylation can lead to dysfunction of glycoproteins, profoundly

influencing cell growth, invasion, metastasis, and immune evasion.

This widespread observation of altered

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glycosylation patterns in cancer cells provides a powerful rationale for developing glycoside amides as highly

selective anticancer agents. By designing compounds that specifically interact with these aberrant glycosylation

signatures, it may be possible to achieve targeted delivery and action against cancer cells, potentially minimizing

the systemic toxicity often associated with conventional chemotherapy.

This approach offers a promising

avenue for precision oncology, where therapies are tailored to the unique molecular characteristics of cancer.

2. Mechanisms of Anticancer Action of Glycoside Amides

The anticancer activity of glycoside amides is attributed to a range of complex mechanisms, from their unique

cellular uptake and intracellular activation pathways to their direct interference with critical cellular processes

and molecular targets. A significant aspect of their therapeutic potential lies in their ability to exploit the distinct

metabolic characteristics of cancer cells.

2.1. Theoretical Insights into Cellular Uptake and Intracellular Activation

Theoretical studies have extensively investigated the intricate processes governing the passage of glycoside

amides through the cell membranes of cancer cells.

These compounds are frequently obtained by modifying

natural glycoside-nitriles, also known as cyano-glycosides.

A key hypothesis emerging from these studies

suggests that it is not the original nitrile glycosides themselves, but rather their amide or carboxyl derivatives,

that possess the primary antitumor properties.

This implies a sophisticated prodrug mechanism where the parent

compound undergoes a series of transformations to yield its active therapeutic form.

Cancer cells exhibit a primary reliance on carbohydrates for their metabolic needs, a fundamental vulnerability

that can be exploited for therapeutic targeting.

Despite this metabolic dependence, cancer cells have evolved

sophisticated defense mechanisms to prevent the passage of external bioactive substances, thereby protecting their

genetic integrity and promoting their continued development.

The theoretical model proposes a multi-step

activation process: initial hydrolysis of the starting nitrile glycosides occurs in the blood medium and the

surrounding physiological environment of both healthy and cancer cells.

Subsequently, a specific molecular

hydrolytic form, the amide or carboxyl derivative, is transferred to the cancer cell membrane, crosses it, and

undergoes a crucial re-hydrolysis within the intracellular environment.

This intracellular re-hydrolysis is critical

because it leads to the formation of bioactive compounds that induce chemical apoptosis, a form of programmed

cell death, independently of the cell's non-genetic mechanisms that attempt to counteract this process.

The conclusion from these theoretical investigations is that amides resulting from the hydrolysis of nitrile

glycosides would possess the unique ability to cross the cancer cell membrane and elicit a targeted cellular

response.

Specifically, amide-carboxyl derivatives of nitrile glycosides are theorized to deliver extremely toxic

compounds directly into the cancer cell, thereby blocking or permanently damaging its normal physiological

functions.

This multi-step activation process—extracellular hydrolysis of the parent compound, followed by

uptake of an intermediate (amide/carboxyl derivative), and subsequent intracellular re-hydrolysis to release toxic

compounds—strongly indicates a sophisticated prodrug strategy. This mechanism leverages the unique

intracellular environment of cancer cells, such as specific enzymatic profiles or pH differences, which are

common considerations in prodrug design

, to selectively activate the drug at the site of action. This targeted

activation enhances specificity and reduces systemic toxicity, representing a significant advancement over non-

selective therapies.

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Furthermore, while cancer cells actively resist the entry of bioactive substances to protect their survival, their

fundamental reliance on carbohydrates for energy presents a crucial weakness. The theoretical model suggests

that glycoside amides, or their hydrolytic precursors, might exploit this metabolic dependency by mimicking

carbohydrates. This mimicry could facilitate their entry into cancer cells, effectively bypassing defense

mechanisms and ultimately delivering a cytotoxic payload. This approach represents an intelligent "Trojan horse"

strategy for targeted therapy, turning a cancer cell's survival mechanism into its vulnerability.

2.2. Induction of Apoptosis and Cell Cycle Modulation

A primary and consistently observed mechanism by which glycoside amides exert their anticancer effects is

through the induction of apoptosis, a form of programmed cell death, and/or the modulation of the cell cycle,

thereby halting uncontrolled proliferation. Despite their diverse chemical origins and structures, a wide array of

glycoside amides, including natural cardiac glycosides, amygdalin, and synthetic flavonoid-based amides and

pyrazole-indole hybrids, consistently converge on inducing apoptosis and/or cell cycle arrest as primary

mechanisms of anticancer action. This indicates that these are fundamental vulnerabilities of cancer cells that

glycoside amides are particularly effective at exploiting, suggesting a broad applicability for this class of

compounds in oncology.

Cardiac glycosides, such as deslanoside, ouabain, digoxin, and digitoxin, have demonstrated significant

anticancer activity. They effectively inhibit colony formation and tumor growth in various cancer cell lines,

including prostate cancer cells (22Rv1, PC-3, DU 145), both in vitro and in vivo (in nude mice).

This inhibitory

effect is mediated by inducing cell cycle arrest, specifically at the G2/M phase, and triggering apoptosis.

Beyond

direct cytotoxicity, some cardiac glycosides have also been shown to kill senescent cells or dissociate clusters of

circulating tumor cells, thereby suppressing metastasis.

Digoxin, in particular, has been reported to induce a

significant increase in apoptosis and cause cell cycle arrest in the G2/M phase in leukemia cells.

Amygdalin, a natural cyanogenic glycoside, has been extensively studied for its anticancer properties. It has been

widely reported to induce apoptosis of cancer cells, inhibit their proliferation, and slow down tumor metastatic

spread across a broad spectrum of cancer types, including lung, breast, prostate, colorectal, cervical, and

gastrointestinal cancers.

Its pro-apoptotic effect is notably mediated via the activation of caspase-3 and increased

expression of BAX protein.

Flavonoid-based amide derivatives, exemplified by compound 7t, have shown promising results in preclinical

studies. This compound caused cell cycle arrest at the G0/G1 phase and induced apoptosis in triple-negative breast

cancer (MDA-MB-231) cells.

Mechanistic investigations revealed that compound 7t achieves its effects by

down-regulating the expression of pro-survival proteins such as phosphorylated PI3K (p-PI3K), phosphorylated

AKT (p-AKT), and Bcl-2, while concurrently up-regulating pro-apoptotic proteins including PTEN, Bax, and

caspase-3.

Pyrazole–indole hybrids, specifically compounds 7a and 7b, have demonstrated potent anticancer activity

against HepG2 (human liver carcinoma) and other cancer cell lines, including HCT-116, MCF-7, and A549.

These compounds were shown to induce cell cycle arrest and apoptosis, affecting key regulatory enzymes and

proteins such as caspase-3, Bcl-2, Bax, and CDK-2.

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A distinct group, Duocarmycins, which are N-glycosyl amides, exert their powerful anticancer effects by directly

disrupting DNA replication and transcription through the formation of covalent bonds with DNA, ultimately

leading to cancer cell death.

While the overarching cellular outcomes of glycoside amides are similar (apoptosis, cell cycle arrest), the specific

molecular targets and pathways through which different glycoside amides achieve these effects vary significantly.

For instance, amygdalin targets Bcl-2 and BAX and activates caspase-3.

Flavonoid-based amides modulate the

PI3K/AKT pathway.

Pyrazole-indole hybrids affect CDK-2.

Duocarmycins directly alkylate DNA.

This

variation in molecular targets signifies that the glycoside amide class is not limited to a single mechanism of

action. This characteristic is crucial for developing personalized therapies, where specific molecular

vulnerabilities in a patient's tumor can be matched with a glycoside amide targeting that particular pathway,

potentially overcoming drug resistance.

2.3. Interaction with Key Cellular Pathways and Molecular Targets

Beyond general cell death, glycoside amides engage with specific cellular pathways and molecular targets that

are crucial for cancer progression and survival. The ability of glycoside amides to engage multiple molecular

targets and pathways, including direct cell signaling and components of the tumor microenvironment, represents

a significant advantage over single-target therapies. This multi-faceted approach is critical for overcoming the

complex and adaptive resistance mechanisms that often develop in cancer, leading to more robust and durable

anti-tumor effects.

Cardiac glycosides are known to modulate multiple signaling pathways.

A well-established mechanism

involves their inhibition of the Na+/K+-ATPase pump, which, while traditionally linked to cardiac effects, also

contributes to their observed anti-tumor properties.

This inhibition disrupts ion gradients essential for cancer

cell function.

Amygdalin has been shown to interact with the active sites of key proteins involved in cell survival and

proliferation, including Bcl-2 and HER2.

It also targets BARD1, suggesting broader protein-interaction

capabilities that contribute to its anticancer effects.

The flavonoid-based amide compound 7t significantly impacts the PI3K/AKT signaling pathway, which is

frequently hyper-activated in many cancers and plays a crucial role in tumor occurrence, development, and

chemoresistance.

Compound 7t achieves its effect by down-regulating phosphorylated PI3K (p-PI3K),

phosphorylated AKT (p-AKT), and the anti-apoptotic protein Bcl-2, while concurrently up-regulating the tumor

suppressor PTEN, and pro-apoptotic Bax and caspase-3.

This coordinated modulation of key regulators within

a central survival pathway underscores its therapeutic potential.

A novel hydrazineyl amide derivative of pseudolaric acid B (compound 12) demonstrates a unique mechanism

by reprogramming tumor-associated macrophages (TAMs).

It shifts TAMs from a pro-tumoral M2-like

phenotype to an anti-tumoral M1-like phenotype, evidenced by decreased CD206 expression, increased CD86

expression, and reduced ARG1 protein levels.

This compound also reverses the suppression of cytotoxic T cell

(CD8+ T cell) proliferation and activation, thereby enhancing the anti-tumor immune response.

Heat shock

protein 90 (Hsp90) has been predicted by target fishing software and further supported by molecular docking as

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a potential molecular target for compound 12, indicating a broader impact on chaperone-dependent protein folding

essential for cancer cell survival.

N-glycosyl-6BrCaQ conjugates, specifically designed as C-terminal HSP90 inhibitors, interfere with HSP90

function.

HSP90 inhibition can disrupt critical signaling pathways, induce cell cycle arrest, inhibit angiogenesis,

and promote cancer cell death.

These glycosylated conjugates exhibited higher biological activity on various

cancer cell lines compared to their non-glycosylated counterparts, suggesting that the sugar moiety enhances their

interaction with the target or improves their delivery.

The widespread overexpression of various glycosidase enzymes within the tumor microenvironment is not just a

general characteristic of cancer but a specific, exploitable molecular target for prodrug activation. These enzymes

include β-glucosidase (upregulated in breast, gastric, liver cancers), Glucosidase II (lung, bladder, gastric,

melanoma), N-Acetyl-β-D-glucosaminidase (ovarian, liver, leukemia, thyroid, breast), α-Glucosidase (liver,

leukemia), β-Galactosidase (solid tumors like liver, ovarian, prostate, colon, breast, gliomas), β-Glucuronidase

(lung, breast, ovarian, pancreatic, colorectal), α-Mannosidase (breast, cervical, ccRCC), and β-Mannosidase

(liver, leukemia).

This implies a rational drug design strategy where the glycoside amide itself functions as a

prodrug, selectively activated by these tumor-specific enzymes to release the cytotoxic payload, thereby achieving

localized drug concentrations and minimizing systemic toxicity. This directly links the enzymatic profile of cancer

cells to the selective efficacy of glycoside-based therapeutics.

2.4. Exploiting Cancer Cell Metabolism and Prodrug Strategies

Cancer cells exhibit a distinct metabolic phenotype known as the "Warburg effect," characterized by increased

glucose uptake and high rates of aerobic glycolysis, even in the presence of oxygen.

This metabolic shift is

accompanied by the overexpression of glucose transporters (GLUTs) on the cancer cell surface

, presenting a

unique vulnerability that can be exploited for targeted therapy. The consistent focus on exploiting the Warburg

effect and the overexpression of GLUTs in cancer cells highlights a fundamental and broadly applicable strategy

for cancer drug delivery. Glycoside amides, by virtue of their inherent sugar component, are uniquely positioned

to utilize this "sugar-guided" delivery mechanism. This offers a built-in advantage for preferential uptake by

tumor cells, potentially leading to higher drug concentrations at the target site and reduced systemic exposure

compared to non-glycosylated agents.

Glycoconjugation strategies leverage this metabolic peculiarity to selectively deliver anticancer therapeutics to

cancer cells.

By attaching anticancer agents to sugar molecules (or other glucose transporter substrates), these

"glycodrugs" can be preferentially taken up by cancer cells that are avid for carbohydrates.

Prodrugs are a key strategy for improving the therapeutic index of anticancer agents. These are inactive

compounds that are designed to release the bioactive substance only under the influence of factors characteristic

of the tumor microenvironment, such as specific enzymes (e.g., glycosidases), lower pH, or hypoxic conditions.

This precise, localized drug release minimizes systemic toxicity and enhances efficacy. Sugars are considered

ideal ligands for obtaining prodrugs that target receptors overexpressed in cancer cells, due to their natural

recognition by cellular transporters and receptors.

Furthermore, polysaccharides can serve as selective

nanocarriers for various chemotherapeutics, providing a versatile platform for drug delivery.

Glycosylated

prodrugs have been shown to improve pharmacokinetic parameters, reduce general side effects, extend drug half-

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life, and potentially lower the required dosage of the active agent.

In the context of nitrile glycosides like amygdalin, theoretical studies hypothesize that the active antitumor forms

are the amide/carboxyl derivatives, which are generated via hydrolysis.

This implies that the initial glycoside

acts as a prodrug, releasing the active amide/carboxyl compound upon enzymatic cleavage.

Glycosidase-activated prodrugs specifically undergo enzymatic bioconversion, where a glycosidase enzyme

cleaves the glycosidic bond, thereby releasing the active anticancer drug at the desired site of action.

This

mechanism is central to minimizing toxic side effects by ensuring that the potent drug is primarily active within

the tumor. Examples of such prodrugs include those designed to release potent cytotoxic agents like

Monomethylauristatin E (MMAE), camptothecin, doxorubicin, vorinostat, paclitaxel, and cyclopamine upon

activation.

The detailed mechanisms of glycosidase-activated prodrugs, including the use of self-immolative

linkers, dual drug release, and various targeting ligands, represent sophisticated chemical engineering solutions.

These designs aim to achieve controlled, on-demand drug release specifically within the unique tumor

microenvironment. This approach directly addresses the critical challenge of balancing drug potency with safety,

leading to a significantly improved therapeutic index by minimizing off-target toxicity while maximizing efficacy

at the tumor site.

3. Preclinical Efficacy and Selectivity of Glycoside Amides

Preclinical investigations have provided substantial evidence for the anticancer efficacy and selectivity of various

glycoside amides, encompassing both naturally derived compounds and synthetic analogs. These studies highlight

the diverse mechanisms through which these agents exert their therapeutic effects.

3.1. Natural Glycoside Amides and Derivatives

Amygdalin, a natural cyanogenic glycoside, has been extensively studied for its anticancer effects. It has

demonstrated activity against a broad spectrum of cancers, including lung, breast, prostate, colorectal, cervical,

and gastrointestinal cancers.

Preclinical studies show its ability to inhibit cancer cell proliferation, induce

apoptosis, and slow down tumor metastatic spread.

A notable aspect of amygdalin's activity is its nuanced dose-

response profile: its anti-metastatic effect in non-small cell lung cancer (NSCLC) cell lines (H1299/M and PA/M)

was observed at lower concentrations than those required for direct proliferation inhibition.

This suggests that

optimal dosing strategies for glycoside amides might vary significantly depending on the desired therapeutic

outcome (e.g., direct tumor cytotoxicity versus prevention of metastatic spread), offering flexibility in clinical

use. Molecular docking and in silico analyses further suggest that amygdalin interacts with key proteins such as

Bcl-2, HER2, and BARD1, providing insights into its molecular targets.

Cardiac glycosides (CGs), a group of naturally occurring compounds, have shown significant anticancer

potential. Examples include deslanoside, ouabain, digoxin, and digitoxin. Deslanoside effectively inhibited

colony formation in vitro and tumor growth in vivo (in nude mice) in prostate cancer cell lines (22Rv1, PC-3, DU

145).

This activity is mediated by inducing cell cycle arrest at the G2/M phase and triggering apoptosis.

Other

CGs have been shown to kill senescent cells, induce apoptosis, or dissociate clusters of circulating tumor cells to

suppress metastasis.

Digoxin, specifically, has been reported to induce a significant increase in apoptosis and

cause cell cycle arrest in the G2/M phase in leukemia cells.

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Vancomycin, a glycopeptide antibiotic, serves as an illustrative example of the crucial role that glycosidic

residues play in biological activity. Its saccharide moieties are essential for its antibacterial activity, and

modifications like N-alkylation of its vancosamine sugar can alter its mechanism and enhance activity against

resistant microorganisms.

This demonstrates the broader potential for glycosidic modifications to improve

therapeutic outcomes in other contexts, including cancer, by enhancing target interaction or overcoming resistance

mechanisms.

3.2. Synthetic Glycoside Amides and Derivatives

Synthetic efforts have expanded the repertoire of glycoside amides with promising anticancer properties, often

demonstrating enhanced efficacy and selectivity over their non-glycosylated counterparts. These compounds are

frequently designed to target specific cancer vulnerabilities.

Flavonoid-based amide derivatives, such as compound 7t, have shown specific cytotoxicity against triple-

negative breast cancer (TNBC) MDA-MB-231 cells, with an IC50 value of 1.76 ± 0.91 µM.

This compound

also demonstrated inhibitory abilities on clonal-formation, migration, and invasion of MDA-MB-231 cells. Its

anticancer activity is achieved by inducing cell cycle arrest at the G0/G1 phase and inducing apoptosis.

Mechanistic studies revealed that compound 7t down-regulates the expression of pro-survival proteins like p-

PI3K, p-AKT, and Bcl-2, while concurrently up-regulating tumor suppressor PTEN, and pro-apoptotic Bax and

caspase-3.

This tailored design for specific cancer vulnerabilities, such as the PI3K/AKT pathway frequently

hyper-activated in TNBC, offers a precision approach to therapy.

Pyrazole–indole hybrids, exemplified by compounds 7a and 7b, demonstrated potent anticancer activity against

HepG2 (human liver carcinoma) with IC50 values of 6.1 ± 1.9 µM and 7.9 ± 1.9 µM, respectively, and also

showed activity against other cancer cell lines including HCT-116, MCF-7, and A549.

These compounds were

shown to induce cell cycle arrest and apoptosis, affecting key regulatory enzymes and proteins such as caspase-

3, Bcl-2, Bax, and CDK-2.

Anthraquinone amide-based derivatives, such as compound MQ3, have been identified as potent Glyoxalase-

I (Glo-I) inhibitors, with an IC50 concentration of 1.45 µM.

The inhibitory potency of MQ3 is attributed to the

synergistic contribution of its catechol ring, amide functional group, and anthraquinone moiety, collectively

contributing to a strong binding affinity with Glo-I.

Targeting Glo-I, an enzyme involved in cancer metabolism,

represents another avenue for anticancer intervention.

Amides-fused isosteviol derivatives have exhibited cytotoxic activities in the low micromolar range against

various cancer cell lines, including those derived from colorectal and other primary and metastatic tumors.

Their

anti-proliferative activities were also found to be cancer cell type specific, indicating potential for selective

targeting.

N-glycosyl-6BrCaQ conjugates, designed as C-terminal HSP90 inhibitors, represent a promising class of

antitumor compounds. These synthetic derivatives demonstrated higher biological activity on various cancer cell

lines compared to their non-glycosylated congeners.

The introduction of the sugar moiety in these compounds

is hypothesized to improve their solubility, selectivity toward cancer cell lines, and pharmacokinetic properties,

thereby enhancing their overall therapeutic profile through HSP90 inhibition.

This exemplifies how the sugar

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moiety can enhance efficacy and selectivity.

A novel hydrazineyl amide derivative of pseudolaric acid B (compound 12) demonstrated potent anti-tumor

macrophage-reprogramming activity.

It effectively inhibited the M2-like polarized tumor-promoting phenotype

of macrophages, evidenced by decreased CD206 expression, increased CD86 expression, and reduced ARG1

protein levels.

This compound also reversed the suppression of cytotoxic T cell (CD8+ T cell) proliferation and

activation, thereby enhancing the anti-tumor immune response.

In in vivo studies, compound 12 inhibited tumor

growth in an immunocompetent Hepa1-6 murine liver cancer model at doses of 25-50 mg/kg, with good tolerance

and no obvious body weight loss.

Hsp90 was predicted and supported by molecular docking as a potential

molecular target for compound 12.

Other synthetic N-glycosyl amides with gluco, galacto, or xylo configurations have been synthesized and

evaluated as inhibitors of β-galactosidase from E. coli, showing moderate inhibitory effects.

Oleyl N-acetyl-α-

and β-d-glucosaminides and their thioglycosyl analogues exhibited antimitotic activity on rat glioma (C6) and

human lung carcinoma (A549) cell cultures in the micromolar range.

In vivo experiments in nude mice bearing

implanted C6 glioma showed that the α-thioglycoside derivative reduced tumor volume, while its O-glycosyl

counterpart was inactive, highlighting the importance of using enzyme-resistant glycosides for in vivo efficacy.

Glycopeptides featuring an unnatural Tn antigen have been developed as cancer vaccine candidates. These

synthetic glycopeptides elicited higher levels of specific anti-MUC1 IgG antibodies in mice and recognized

human breast cancer cells with high selectivity in vivo, demonstrating their potential for immunotherapy.

Glycoconjugates of 8-hydroxyquinoline derivatives have shown cytotoxicity against cancer cell lines (HCT

116, MCF-7) and inhibition of β-1,4-galactosyltransferase activity, which is associated with cancer progression.

The presence of additional amide groups in the linker structure improved the activity of these glycoconjugates,

possibly due to their ability to chelate metal ions often present in cancers.

Finally, anthracycline glycosides with the daunorubicin scaffold were tested against human cancer cell lines

(HeLa, MDA-MB-231, MCF-7) and a model of healthy cells (HDF). The α anomer showed IC50 values in the

range of 27.1 to 74.6 µM, while the β anomer was significantly less potent (IC50 > 250 µM), illustrating the

importance of stereochemistry for activity.

4. Pharmacokinetics and Bioavailability Considerations

The journey of a drug from administration to its site of action involves complex processes of absorption,

distribution, metabolism, and excretion (ADME). For glycoside amides, the sugar moiety plays a crucial role in

influencing these pharmacokinetic parameters, impacting their overall therapeutic efficacy and safety profile.

4.1. Impact of Glycosidic Modifications on ADME

Glycosylation, the process of attaching a sugar unit, can profoundly improve various pharmacokinetic parameters,

including solubility, transport across biological membranes, and overall bioavailability.

This is a critical

consideration in drug design, as many potent anticancer agents suffer from poor aqueous solubility, limiting their

formulation and systemic delivery. N-glycosyl amides, in particular, often exhibit enhanced stability towards

enzymatic degradation compared to other glycoside types.

This increased stability can prolong their half-life in

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the bloodstream, allowing for sustained therapeutic exposure.

Carbohydrates generally contribute to high aqueous solubility, low inherent toxicity, and high biocompatibility,

making them attractive components for drug delivery systems.

Glycosylated prodrugs, designed to release an

active drug upon specific enzymatic cleavage in the tumor microenvironment, can significantly reduce systemic

side effects and extend the drug's half-life by preventing premature activation.

For flavonoid glycosides, which are a broad class of natural products, general trends indicate greater

hydrophilicity and lower lipophilicity compared to their corresponding aglycones (non-sugar parts).

This often

translates to improved stability but, paradoxically, can sometimes lead to lower bioavailability, although this is

not an absolute rule, as certain C-glycosides can exhibit higher plasma concentrations than their aglycones.

The absorption mechanisms for flavonoids illustrate the complexity: some are converted to their aglycone forms

by enzymes like lactase phlorizin hydrolase (LPH) in the small intestine, allowing passive diffusion due to

increased lipid solubility.

Alternatively, hydrophilic glycosides can be transported by membrane transporters

such as sodium-dependent glucose transporter 1 (SGLT-1) and glucose transporter 2 (GLUT-2), followed by

intracellular hydrolysis to their aglycones for absorption.

Once absorbed, flavonoids undergo extensive hepatic metabolism through phase I hydroxylation and phase II

reactions (glucuronidation, sulfation, and methylation).

These metabolic modifications primarily increase the

water solubility of the compounds, facilitating their excretion through the kidneys or bile and simultaneously

limiting their toxic potential.

For amygdalin, a natural cyanogenic glycoside, there is a recognized need for non-toxic formulations due to its

cyano-moiety, which can lead to adverse side effects.

Nanoparticles have emerged as a promising alternative to

enhance amygdalin's anticancer effects while simultaneously reducing its systemic toxicity, showcasing a strategy

to overcome bioavailability limitations and improve the therapeutic index.

The hydrazineyl amide derivative of pseudolaric acid B (compound 12), a synthetic glycoside amide,

exhibited specific pharmacokinetic properties in mice: a half-life of 40.2 hours, a quick peak time (Tmax) of

0.083 hours, a peak plasma concentration (Cmax) of 32.1 ng/mL, and an area under the curve (AUC0–∞) of 363

h·ng/mL, with a high systemic plasma clearance of 2766 mL/hr/kg.

These properties were considered suitable

for further in vivo anticancer evaluation, demonstrating that synthetic modifications can yield compounds with

favorable pharmacokinetic profiles.

The impact of glycosylation on ADME properties highlights a crucial aspect of glycoside amide drug

development: balancing solubility, stability, and bioavailability. While adding sugar moieties generally increases

hydrophilicity and stability, it can sometimes reduce passive membrane permeability, affecting absorption. This

necessitates a careful optimization of glycosylation patterns to achieve the desired ADME profile for specific

therapeutic applications. This optimization process represents a key challenge and opportunity in designing

effective glycoside amide-based therapeutics.

Furthermore, the strategic design of prodrugs for controlled release and reduced toxicity is a core principle in the

development of glycoside amides. By leveraging the unique enzymatic and physiochemical characteristics of the

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When defining the topic, all of our articles and studies were intentionally removed in order not to affect the focus of the answers.

* Google Gemini | Deep Research

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tumor microenvironment, these prodrugs can be engineered to remain inactive in systemic circulation but release

their potent payloads precisely at the tumor site. This targeted activation significantly improves the therapeutic

index by minimizing off-target toxicity while maximizing drug concentration and efficacy where it is most

needed.

5. Clinical Translation and Future Directions

The journey from promising preclinical data to successful clinical application is often long and fraught with

challenges. For glycoside amides, while preclinical studies have shown significant potential, their clinical

translation is still in nascent stages, with considerable opportunities for future development.

5.1. Current Status of Clinical Trials

Clinical trials specifically focusing on glycoside amides as anticancer agents remain limited. Theoretical studies,

however, suggest a transformative potential for these compounds, proposing that their application in oncology

could convert cancer from a lethal disease into a manageable chronic condition, akin to diabetes.

This visionary

outlook underscores the high hopes placed on this class of compounds.

Among natural glycosides, cardiac glycosides like digoxin and deslanoside have seen some investigation into

their anticancer effects in clinical trials.

Deslanoside, for instance, had not been tested for its anticancer effect

in prostate cancer until recently, indicating a growing interest in repurposing existing drugs with known safety

profiles for oncology.

For galectin inhibitors, some of which are N-glycosyl amides or glycomimetics, clinical trials have reported

inconclusive results to date.

Nevertheless, preclinical data continue to show promise, especially when these

inhibitors are used in combination therapies.

Specific examples include TD139 (also known as GB0139), which

has been evaluated in a clinical trial for idiopathic pulmonary fibrosis (NCT02257177).

Another compound,

GB1211, which shares a chemical template with GB1107, has completed Phase I studies (NCT03809052) and is

advancing into safety and efficacy clinical studies in combination with atezolizumab for non-small-cell lung

cancer (NCT05240131).

These ongoing trials, though not exclusively focused on the amide linkage, highlight

the broader exploration of glycosylated compounds in cancer.

In the realm of antibody-drug conjugates (ADCs), which often leverage glycosylation for improved properties,

Fc-glycan conjugation has shown promising results in Phase I trials, with compounds like JSKN003 and IBI343

advancing to Phase III studies.

This approach offers improved ADC homogeneity, enhanced pharmacokinetics

and therapeutic index, and potentially reduced Fc receptor-mediated side effects.

Glycosylation is crucial for

the properties and effector functions of monoclonal antibodies, making it a key area of development for targeted

cancer therapies.

Despite the preclinical promise, amygdalin, a widely studied natural cyanogenic glycoside, has very few in vivo

animal studies and even scarcer human clinical studies reported.

This significant gap between preclinical

findings and clinical reality underscores the need for more robust in vivo and human clinical studies to fully

explore its potential prevention and/or treatment efficiency against cancer.

This challenge applies broadly to

many novel compounds, including glycoside amides, where translating promising preclinical data into successful

clinical outcomes requires substantial investment and rigorous testing.

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5.2. Challenges and Opportunities in Drug Development

The development of glycoside amides as anticancer agents faces several challenges, yet these also present

significant opportunities for innovation.

Challenges:

● Synthesis: As previously discussed, the synthesis of N-glycosyl amides is often plagued by low yields,

susceptibility to hydrolysis, loss of stereocontrol through anomerization, and the potential reliance on

hazardous reagents.

Furthermore, large-scale chemoenzymatic glycoengineering, while promising, faces

issues related to activated sugar donors, high economic costs, complex purification processes, sustainability

concerns, unproductive oxazoline hydrolysis, non-enzymatic glycation, and stringent regulatory hurdles.

● Toxicity and Selectivity: A major limitation of conventional anticancer drugs is their lack of specificity,

leading to significant side effects on healthy cells, such as myelosuppression, mucositis, hair loss,

cardiotoxicity, neurotoxicity, and immunosuppression.

This often necessitates large doses, further

exacerbating adverse effects.

Compounding this, cancer cells frequently develop resistance to available

drugs, limiting long-term efficacy.

● Pharmacokinetics and Bioavailability: Many bioactive compounds, including flavonoids and their

glycosides, often exhibit low bioavailability due to their structural characteristics, which can impede optimal

absorption, metabolism, and distribution in the body.

● Clinical Translation: The inconclusive results from some clinical trials, such as those for galectin inhibitors

, highlight the complexities of translating preclinical success. For compounds like amygdalin, the scarcity

of in vivo animal and human clinical studies remains a significant barrier.

Additionally, the complex

structures and catabolism of advanced drug conjugates (e.g., ADCs) can complicate payload delivery and

lead to off-target uptake, affecting their overall efficacy and safety.

Opportunities:

● Targeted Therapies: The unique biological landscape of cancer cells, particularly their altered glycosylation

patterns and overexpressed glycosidases, presents a prime opportunity for developing highly targeted

therapies. Glycoside amides can be designed as prodrugs that are selectively activated by these tumor-

specific enzymes, leading to localized drug concentrations and minimizing systemic toxicity.

This

approach directly addresses the critical challenge of balancing drug potency with safety, leading to a

significantly improved therapeutic index.

● Prodrug Design: The development of prodrugs that release bioactive substances only under the influence

of factors characteristic of the tumor microenvironment (e.g., specific enzymes, lower pH, hypoxia) is a

powerful strategy to minimize systemic toxicity and enhance efficacy.

● Glycomimetics: Designing molecules that mimic carbohydrates but possess enhanced stability and enzyme

inhibitory properties offers a way to overcome the limitations of natural compounds.

● Multi-Targeting and Immunomodulation: Strategies that enable glycoside amides to engage multiple

cellular pathways and elicit immune responses can be crucial for overcoming the complex and adaptive

resistance mechanisms that cancer cells develop.

● Advanced Synthesis: Innovations such as radical-based approaches for N-glycosylation

and

chemoenzymatic glycoengineering for producing homogeneous glycan profiles in therapeutic monoclonal

antibodies

are vital for scalable and precise compound production.

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● Nanocarriers: The use of polysaccharides and other nanoparticles as selective drug delivery vehicles can

significantly improve the pharmacokinetics, efficacy, and safety of anticancer agents by enabling targeted

delivery and controlled release.

● Computational Approaches: The integration of advanced computational methods, including artificial

intelligence (AI) and machine learning (ML) for screening and predicting therapeutic efficacy

, and

molecular docking, QSAR, and molecular dynamics simulations for understanding binding interactions and

optimizing compounds, is accelerating drug discovery and design.

● Repurposing: Identifying existing glycosides with established safety profiles, such as cardiac glycosides,

for anticancer repurposing offers a faster path to clinical application by leveraging existing knowledge and

reducing development time.

5.3. Future Research Directions and Prospects

The future of glycoside amides in oncology is poised for significant advancements, driven by a convergence of

technological innovations and a deeper understanding of cancer biology. The shift towards precision oncology

will increasingly focus on highly specific, patient-tailored therapies.

A critical need remains for further in vivo animal and human clinical studies for natural glycoside amides like

amygdalin to establish their definitive therapeutic value and safety profiles.

Research should also explore the

potential benefits of combined intake of natural nitrile glycosides and their amide/carboxylic acid forms, as

theoretical studies suggest these derivatives are the active anticancer agents.

This necessitates the optimization

of pharmaceutical formulations to ensure the precise ratio of active amide/carboxylic acid forms for optimal

therapeutic effect.

Continued development of targeted therapies that exploit cancer-specific receptors and the unique tumor

microenvironment is paramount.

This will increasingly involve multi-compound, multi-target, and multi-

pathway approaches to overcome the complex and adaptive nature of cancer resistance.

Advancements in synthetic methodologies for N-glycosyl amides are crucial to overcome current synthesis

challenges, enabling the scalable and cost-effective production of novel drug candidates.

Leveraging aberrant

glycosylation patterns as biomarkers for early diagnosis, prognosis, and guiding treatment strategies will also be

a key area of focus.

The repurposing of existing glycosides with known safety profiles for oncology applications presents a valuable

opportunity for accelerated drug development.

Furthermore, the development of "biobetter" antibodies through

advanced glycoengineering techniques holds promise for creating more effective and safer immunotherapies.

Finally, computational methods, including AI-driven tools like AlphaFold for protein structure prediction, along

with QSAR and molecular dynamics simulations, will play an increasingly vital role in accelerating the discovery,

design, and optimization of novel glycoside amide anticancer agents.

This holistic drug development paradigm,

integrating insights from synthesis, biology, pharmacology, and computational science, will be essential for

realizing the full therapeutic potential of glycoside amides in oncology.

Conclusions

AI* generated deep learning on the topic: Anticancer Activity of Glycoside Amides 
 
When defining the topic, all of our articles and studies were intentionally removed in order not to affect the focus of the answers. 
* Google Gemini | Deep Research 
14 
https://www.anti-cancer.eu 
Glycoside amides represent a highly promising class of compounds with diverse and potent anticancer activities. 
Their  unique  chemical  structures,  particularly the  N-glycosidic  amide  linkage,  confer  distinct  advantages  in 
biological  interactions and  stability.  Preclinical  evidence  strongly  supports  their  ability  to  induce  apoptosis, 
modulate the cell cycle, and interact with key molecular targets and pathways critical for cancer progression. A 
significant strength of these compounds lies in their potential to exploit cancer-specific metabolic vulnerabilities, 
such as the Warburg effect and overexpressed glycosidases, through sophisticated prodrug strategies. This allows 
for targeted drug delivery and activation within the tumor microenvironment, offering a path to enhanced efficacy 
with reduced systemic toxicity. 
While challenges in synthesis, pharmacokinetics, and the translation of theoretical and preclinical findings into 
successful clinical outcomes persist, ongoing advancements are rapidly addressing these hurdles. Innovations in 
synthetic methodologies, the development of advanced prodrug designs, the application of multi-targeting and 
immunomodulatory approaches, and the increasing integration of computational tools are collectively paving the 
way for a new generation of glycoside amide-based therapeutics. The strategic design of these compounds to 
leverage the unique biological landscape of cancer cells positions them as vital components in the future of 
precision  oncology,  holding  the  potential  to  transform  cancer  from  a  life-threatening  disease  into  a  more 
manageable chronic condition. Continued rigorous research and collaborative efforts across disciplines will be 
essential to fully realize this therapeutic promise. 
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