422 exam3 carbohydrates

Reduced monocarbohydrates – applications

Osmotic diuretics, laxatives, humectants/thickeners, tweens/spans

Factors that increase carbohydrate solution viscosity

↑Hydrogen bonding, ↑molecular size, ↑concentration, ↑chain length

Why mono- & some disaccharides are unsuitable for drug formulation

Rapid glycolysis due to carbonyl instability; convert to polyols to increase stability.

Carbohydrate → Polyol conversions

Glucose→sorbitol; mannose→mannitol; xylose→xylitol; glyceraldehyde→glycerol.

Osmotic diuretics (mannitol/isosorbide)

Slowly/non-metabolized carbohydrate derivatives; increase blood osmolarity; reduce intracranial & intraocular pressure.

Glycerol – application

Humectant and thickener.

Sorbitol – application

Laxative.

Spans/Tweens – detergent use

Hydrophobized sorbitan derivatives used as emulsifiers/stabilizers.

Tween vs Span

Tween = more hydrophilic (high HLB); Span = more lipophilic (low HLB).

ISDN/ISMN

Nitrated isosorbide derivatives used for angina.

Fructose vs glucose (satiety)

Fructose causes less satiety → promotes increased food intake.

Sweet sensors for sugars

T1R2/T1R3 GPCRs.

Why saccharin tastes bitter

Can bind to nociceptors.

Sucralose (Splenda)

Halogenated disaccharide; 600× sweeter than sucrose; poorly absorbed & not metabolized.

Cyclamate

30–50× sweeter; used to mask drug bitterness; banned in US but approved in 55 countries.

Saccharin

300× sweeter; bitter aftertaste; unstable when heated; zero-calorie.

Steviol (Stevia/Truvia)

300× sweeter; bitter aftertaste; glycemic index ≈ 0.

Artificial sweeteners – benefits

Aid weight loss; better glycemic control; prevent dental caries; may cause reactive hypoglycemia.

Glycosidic bond α vs β

α = trans; β = cis addition around anomeric carbon.

Salicin

Analgesic/anti-inflammatory; metabolized to salicylic acid; glucose = glycone, ArOH = aglycone.

Amygdalin

Glycoside found in bitter almonds and some kernels.

Ouabin

Cardiac glycoside from foxglove; Na/K pump inhibitor; contains L-rhamnose.

Quercetrin

Flavonoid glycoside; dye; antioxidant; kinase inhibitor.

Lactulose structure

Galactose-β(1→4)-fructose.

Lactulose – effects

Laxative & ammonia reducer; not absorbed; metabolized to acids that neutralize ammonia.

Lactulose contraindication

Patients with β-galactosidase deficiency.

Glycan diversity

Each –OH can form α or β linkages; polymers may be branched or linear.

Glycocalyx

10–100 nm glycan layer on all cells used for recognition/communication.

Two major carb-drug targets

Glycolytic enzyme inhibitors (obesity) & glycoside-binding protein inhibitors (infections).

Why monosaccharides bind weakly

Protein binding sites filled with water; displacement of few water molecules gives low affinity.

Alpha-amylase inhibitors (AAIs)

Lower post-meal glucose spikes; iminosugars mimic transition state.

Antivirals (Tamiflu/Zanamivir)

Designed from sialic acid; inhibit neuraminidase → prevents viral release.

UTI carbohydrate therapy

α-mannosides (e.g., cranberry) block UPEC adhesion.

Carbohydrate-based vaccines

Carbohydrate antigens ligated to polypeptide carriers; limited by low immunogenicity.

Cyclodextrins (CDs)

Cyclic α(1,4) glycans; hydrophobic cavity binds drug; hydrophilic exterior prevents membrane crossing.

Cyclodextrin uses

Enhance stability/bioavailability; convert oils to powders; reduce taste/odor; prevent incompatibilities.

Polysaccharide properties

High MW; amorphous; non-sweet; non-reducing; generally insoluble.

Cellulose linkage

β(1→4) D-glucose polymer.

Why mammals can’t digest cellulose

Extensive intra/inter-chain H-bonding blocks glycosidase activity.

Cellulose derivatives – uses

Microcrystalline cellulose (binder), methylcellulose (suspending agent, laxative), Na-CMC (lubricant, toothpaste), cellulose acetate (film), CAP (enteric coating), nitrocellulose (explosives).

Starch components

Amylose + amylopectin (α1,4; amylopectin branched at α1,6 every 12–30 units).

Starch uses

Storage polysaccharide, fuel source, excipient, industrial use.

Starch iodine test

Turns blue

Glycogen

Highly branched (α1,4 & α1,6 every 8–12 units); “animal starch.”

Inulin

β(2,1) fructose polymer; soluble dietary fiber; probiotic; immune-activating; used as vaccine adjuvant (Advax).

GAG general features

Long linear chains; repeating disaccharides; O-linked to proteins; acidic groups.

Chitin structure 

β(1,4) N-acetylglucosamine polymer.

Chitosan

Deacetylated chitin; preserves food by binding Fe and slowing rancidity.

Hyaluronic acid function

Lubricant; joint protection; shock absorber; viscoelastic.

Hyaluronic acid function

Lubricant; joint protection; shock absorber; viscoelastic.

Hyaluronic acid applications

OA treatment, eye drops, surgical adjuncts, cosmetics.

Heparin structure

Sulfated glucosamine + sulfated glucuronic/iduronic acid dimers.

Heparin MOA

Binds antithrombin → induces conformational change → inhibits Factor Xa → prevents clotting.

Fondaparinux

Synthetic pentasaccharide version of heparin.

Cancer cell characteristics

Rapid, abnormal cell division with poor repair mechanisms.

Why combination chemotherapy is preferred

Fights acquired resistance; uses multiple mechanisms to increase effectiveness.

Major groove characteristics

Rich in basic atoms; allows sequence-specific binding.

Minor groove characteristics

Hydrophobic ribose H atoms; A/T-rich; sequence-nonspecific; mainly shape recognition.

Minor groove binder characteristics

Long, planar, crescent-shaped; bind A/T; hydrophobic with H-bonding.

Minor groove binder activity

Antimicrobial & antitumor.

Minor groove binders reversible action

Block protein access to DNA.

Minor groove binders irreversible action

Alkylation of bases (e.g., duocarmycins).

Methylproamine

Minor groove binder; radioprotector and DNA stain.

Netropsin

Minor groove binder that binds A/T-rich regions.

Major groove binders overview

Mainly proteins that alter DNA structure.

C2 repressor 

Major groove binder causing small distortion.

TATA-binding protein

Major groove binder causing major DNA distortion.

Platinum drug mechanism

Form covalent intra-strand crosslinks via N-atom binding → inhibits transcription → apoptosis.

Examples of platinum anticancer drugs

Cisplatin, carboplatin, oxaliplatin, phenanthriplatin.

Intercalator mechanism

Reversible insertion between DNA bases; separates strands.

Intercalator example

Dynemycin.

Electrostatic binder mechanism

Reversible binding of (+)-charged molecules to (-)-charged DNA backbone.

DNA alkylator mechanism

Electrophiles that form covalent adducts with nucleophilic DNA sites.

Most common result of DNA alkylation

Strand scission from glycosidic bond instability.

Secondary cancer risk

Many alkylators can cause secondary cancers post-remission.

Bifunctional alkylator effect

DNA crosslinking → prevents separation and replication.

EWG effect on alkylators

EWGs lower nucleophilicity and reduce reactivity (R).

Importance of nitrogen nucleophilicity

Critical for alkylator activity.

Mechanism of strand scission

Alkylation weakens glycosidic bond → β-elimination → DNA break.

Role of topoisomerases

DNA winding/unwinding during replication; without them replication stops.

Topo I vs Topo II

Topo I breaks 1 strand; Topo II breaks both strands and removes 2 positive supercoils per cycle.

TOPO covalent intermediate

Enzyme forms a covalent bond with DNA during its mechanism.

Requirement for TOPO inhibition

Must intercalate AND stabilize cleavable TOPO–DNA complex.

Effect of stabilized TOPO–DNA complex

Prevents re-ligation; causes lethal DNA strand breaks.

D-Actinomycin

Intercalator that stabilizes TOPO cleavable complex; antitumor agent.

Topotecan

Topoisomerase I inhibitor; cancer cells may develop resistance.

“-rubicins” mechanism

Anthracyclines generate hydroxyl radicals → DNA strand cleavage.

Examples of rubicins

Doxorubicin, idarubicin, daunorubicin.

Antisense DNA purpose

Complementary to mRNA; blocks translation.

Properties of antisense drugs

Synthetic, nuclease-resistant DNA oligomers; form stable duplexes with DNA/RNA.

Diseases treatable by antisense therapy

Any condition caused by gene overexpression.

Major challenge of antisense therapy

Delivery due to high negative charge, high MW, and cost.

Examples of antisense drugs

Etlepirsen (DMD), Mipomersen (icosamer).

Duocarmycins

Minor groove binders activated by conformational change after binding.

Mitomycin

Drug activated by metabolic reduction.

Dacarbazine

Drug activated by P450 hydroxylation.

Leinamycin

Drug activated metabolically through thiol reactions.

Hydroxyl radical–forming drug classes

Anthracyclines, bleomycin, enediyne antibiotics.

Effect of hydroxyl-radical–forming drugs

Create DNA radicals → DNA scission and lesions.

Drugs affecting DNA synthesis

Thymidylate synthase inhibitors, reverse transcriptase inhibitors, epigenetic modulators.