Med Chem Midterm

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Topo I Inhibitors

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Camptothecins (irenotecan)

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Topo II Inhibitors

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Anthracyclines (Daunorubicin & Doxorubucin)

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Reason to use Topo Inhibitors for cancer treatment

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Dividing cells require great activity due to increase DNA synthesis

act by stabilizing the DNA topo complex

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MOA of Topo I inhibitors

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Topo I wraps around DNA and makes a cut allowing helis to spin and then reconnects broken strands when relaxed.

DNA will be cleaved but not re-ligated when relaxed - causes single strand breaks in DNA

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Required structure of camptothecins

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intact lactone

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MOA of TOPO II inhibitors

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Topo II cleaves both strands of DNA helix to manage DNA tangles and supercoils (use ATP)

target DNA-protein complex - increased cleavage and some inhibit re-ligation = accumulation of non-reversible DNA double strand breaks

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Metabolism of Irenotecan

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*Prodrug*
hepatic: carboxylesterase (CE) = SN-38 (active)
UGT1A1/7 = SN-38 to SN-38G
CYP3A4 = NPC (Active) and APC (inactive)

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SN-38

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Active metabolite of irenotecan that is responsible for anti-tumor action

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Pharmacogenomics of irenotecan

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UGT/A1*28 - decreased UGT1A/7 - increases SN-38 and APC (Increased toxicity)

can give lower dose but usually use other drug

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Overall structure of anthracyclines

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4 6-membered rings with L-daunosamine (therapeutic)

2 phenolic groups and quinone function

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part of anthracyclines that is required for therapeutic action

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L-daunosamine

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MOA of anthracyclines

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**high affinity for DNA
1) intercalate the major groove between base pairs of DNA double helix (cell will try to repair - when too severe = apoptosis)
2) inhibit topo II - preventing relaxing of DNA and blocking DNA transcription and replication
3) excessive DNA damage (formation of reactive oxygen species)

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Not therapeutically useful things anthracyclines binds to

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1) RNA
2) Proteins
3) Lipids

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Metabolism of Anthracyclines

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*extensively metabolized*
1) reduction of side-chain carbonyl to secondary alcohol by keto-aldo reductase
2) hydrolysis of amino sugar by liver NADPH-dependent P-450 reductase - inactive aglycones (highly toxic hydroxyl radicals)

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Anthracycline Toxicities

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1) Bone marrow toxicity (myelosuppression) - DLT
2) Cardiotoxicity - immediately after admin
3) chronic cardiotoxicity - up to 6 months after admin

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Resistance to anthracyclines

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1) Intrinsic - acquired during repeated courses of treatment
2) Acquired dependent unidirectional outward drug pumps (PgP, MRP, BCRP)

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Administration of Doxorubicin and Daunorubicin

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IV formulation

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Idarubucin

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1) lack methoxy group in four-ring anthracycline structure - yellow color and increase lipophilicity
2) Can pass the BBB
3) Can be given orally but not FDA approved

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Advantages of the liposomal formulation of doxorubicin

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1) circulation half life is 2-3 days (vs 5 mins)
2) concentration of drug within tumors can be 6x greater
3) tumor targeted efficacy without toxicities

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Structure of Bleomycin

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1) Metal binding domain (Chelation)
2) DNA binding domain
3) Carb domain

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MOA of Bleomycin

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1) aromatic dithiazole ring system - intercalates DNA - DOES NOT inhibit Topo II
2) intercalation position drug for DNA destruction by cytotoxic free radicals
3) chelates metal ions = pseudo-enzymes react with oxygen to produce free radicals
4) may also inhibit incorporation of thymidine into DNA strands

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Requirements for Bleomycin to work

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dependent on intracellular pH
requires a metal ion cofactors

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Bleomycin toxicities

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1) Chronic skin reactions (hyperpigmentation of trunk, hyperkeratosis, erythema, ulceration
2) Pulmonary fibrosis - most serious and lethal - DLT

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Bleomycin resistance

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drug inactivated by its hydrolase - enzyme that catalyses hydrolysis of specific amide grps from intact peptide

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reason to target tubulin and microtubules in cancer treatment

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microtubules are important for maintain cell structure

agents bind tubulin and inhibit polymerization ro bind microtubules inhibiting depolymerization - reduced dynamic movement of chromosomes (block mitosis)

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Antimitotic agents

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1) Vinca alkaloids
2) Taxanes
3) Epothilones
4) Miscellaneous

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Vinca Alkaloids

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1) Vinblastine
2) Vincristine
3) Vinorelbine

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Taxanes

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1) Paclitaxel
2) Docetaxel
3) Cabazitaxel

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Epothilones

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Ixabepilone

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Miscellaneous Antimitotics

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1) Eribulin
2) Brentuximab vedotin

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3 binding sites of drugs to tubulin

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1) Vinca Site (Vinca alkaloids, eribulin) - plus end
2) Colchicine Site (Colchicine) - intra-dimer interface
3) Taxol Site (Paclitaxel, Docetaxel, Epothilone, Exabepilone) - inside surface of hte membrane

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Structure of Vinblastine

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Bisindole alkaloid - CH3 on vindoline nucleus

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Structure of Vincristine

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Bisindole alkaloid - CHO on vindoline ring

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Structure of Vinorelbine

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Bridge linking indole ring to piperidine nitrogen is shortened by 1 carbon

molecule of water eliminated from piperidine ring

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Administration of ALL vinca alkaloids

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IV

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ADR for Vinblastine

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myelosuppression - DLT

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ADR for Vincristine

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peripheral neurotoxicity - DLT

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ADR for vinorelbine

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Myelosuppression - DLT
**severe neutropenia in ~ 50% of patients**

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Vinca Alkaloid that crosses BBB

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Vincristine

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Paclitaxel

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1) 15 membered tricyclic taxane ring
2) extremely hydrophobic - requires Cremophor EL (active and cause ADRs)
3) effectiveness limited by affinity for PgP

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Docetaxel

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C10 function group change = more water soluble but still requires Tween 80 surfactant (ADRs)

Poor bioavailability

Peripheral neuropathy and myelosuppression - DLTs

Effectiveness limited by affinity for PgP

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nab-paclitaxel

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1) nanoparticle albumin bound
2) Advantages: shorter infusion time, predictable PK, more drug delivered to cancer cells, CREMOPHOR free

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Cabazitaxel

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1) Elimination of P-gP affinity - effective against docetaxel-refractory cancer
2) can cross BBB
3) still requires Tween 80

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ixabepilone

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1) critical structure: macrolide ring with thiazole-containing side chain and a ketone
2) primary ADRs: neutropenia and neuropathy
3) More resistant to degradation by carboxylesterase
4) requires cremaphor

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Brentuximab

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Chimeric monoclonal antibody

binds CD30 and targets drug to cell

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Vedotin

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antimitotic agent

synthetic analog of tubulin polymerization inhibitor dolastatin 10

binds tubulin binding site - serves as tubulin polymerization inhibitor

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Mechanism of resistance for antimitotic agents

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1) cellular efflux (PgP overexpression)
2) altered drug metabolism
3) alteration in tubulin or microtubules
4) deficient induction of apoptosis

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Antimitotic agents not substrates for P-gP

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Ixabepilone

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Apoptosis

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1) Extrinsic - activation of "death" receptors
2) Intrinsic - mediated by mitochondria (DNA damage)
3) Final step - caspase cascade = cleaves regulatory and structural molecules leading to cell death

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General features of apoptosis

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1) occupation of death receptors
2) Dimerization of Bcl-2 family members
3) Release of cytochrome C
4) activation of caspases
5) activation of DNase

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Degradation of a protein through ubiquitin proteasome pathway

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majority of intracellular proteins degraded

utilizes several enzymes to link chains of ubiquitin into proteins

tagging process leads to recognition by proteasome

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3 enzymes that must be working in ubiquitin proteasome pathway

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E1 ubiquitin-activating enzyme - modify ubiquitin
E2 ubiquitin-conjugating enzyme - catalyze attachment of ubiquitin to protein
E3 ubiquitin ligase - in concert with E2, recognize protein

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Proteasome structure

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26S complex = central barrel shaped 20S proteasome catalytic core with 19S regulatory particle

20S proteolytic core - hollow cylinder

2 outer alpha rings and 2 inner beta rings

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Structure of Bortezomib

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Tripeptide = pyrazonoic acid, phenylalanine, Leucine w/ boronic acid

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Bortezomib

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*selectivity for 26S proteasome*
1) inhibition of formation of a reversible dipolar bond between Nterminal Threonine and Boron atom
2) metabolized by CYP3A4 to inactive metabolites
3) Major DLT = peripheral neuropathy
4) Consequences = inhibits activation of NF-kB
5) Limitations = resistance in ~1 year

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Structure of Carfilzomib

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tetrapeptide epoxyketone (no boron)

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Carfilzomib

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1)binds irreversibly and inhibits 20S proteasome
2) inhibition of proteasome-mediated proteolysis - build up of poly-ubiquinated proteins and leads to cell cycle arrest, apoptosis, inhibits tumor growth
3) no activity against off-target enzymes like SERINE proteases
4) low incidence of peripheral neuropathy

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L-asparaginase

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*starves the cell*
1) Asparagine is crucial amino acid for protein, DNA, RNA synthesis and required in G1 phase
2) lymphoblasts lack asparagine synthetase and relies on exogenous asparagine
3) Drug prevents asparagine from getting to cell

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Role of histones

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our genome wraps around them - tagged by enzymes with acetyl and methyl (determines which genes are switched on/off)

changes in behavior of HDAC plays role in cancers by switching on wrong genes

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Gene Switched ON

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active (open) chromatin

unmethylated cytosines

Acetylated histones

Loose - open

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Gene switched OFF

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silent (condensed) chromatin

methylated cytosines

Deacetylated histones

tightly packed

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Retinoids

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1) Tretinoin
2) Alitretinoin
3) Bexarotene

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Tretinoin

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1) naturally ocurring Vitamin A derivative
2) Binds with high affinity to RARs (no affinity for RXRs)
3) Retinoic Acid Syndrome - fever

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Alitretinoin

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1) 9-cis-retinoic acid (isomerization of tretinoin)
2) Binds to all 6 receptors (RARs and RXRs)
3) regulates proliferation
4) Requires thyroid hormone replacement
5) produces anti-inflammatory response

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Bexarotene

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1) Binds selectively to RXRs
2) Induces apoptosis in variety of in vitro and in vivo models
3) Administered orally and topically
4) Generally well tolerated
5) Requires thyroid hormone replacement

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Denileukin deftitox

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*Fusion Protein*
1) IL-2: responsible for selective delivery
2) Diphtheria toxin: responsible for cytotoxicity
3) binding to IL-2R followed by internalization and cell death through inhibition of ADP ribosylation of EF2

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Synergy of denileukin deftitox and bexarotene

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Bexarotene up-regulates IL-2R expression

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MOA of HDAC (histone deacetylase) inhibitors

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inhibits HDAC = histone acetyl-transferase can activate gene transcription resulting in chromatin uncoiling and activation of gene transcription

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Vorinostat

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Blocks substrate access to the active zinc ion at its base

chelates zinc ion in the active site through hydroxamic acid moiety

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Romidepsin

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Disulfide bond becomes reduced by glutathione to an active compound with free sulfhydryl moeity that binds the zinc in HDAC active site

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DNA methyltransferase Inhibitors

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cancer cells inactivate tumor-suppressor genes by hypermethylating CpG islands

inhibit DNMT - reverses hypermethylation - leading to reactivation of tumor suppressor genes and killing tumor cells

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MOA of 5-Azacytidine

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incorporated into DNA - suicide inhibitor of DNMT

induces global hypomethylation

GIVEN BY INJECTION (poor oral absorption)