Med Chem Ii Exam 2- Anti-Cancer I

Front 1

neoplasms definition

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new and diseased form of tissue growth. Benign
neoplasms are not cancerous while malignant neoplasms are. The key distinction between
these two terms is that only malignant tumors metastasize.

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suffix -oma for cancer- meaning

2 exceptions to this rule

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usually indicates a benign tumor such as adenoma (glandular
epithelium), chondroma (cartilage) or osteoma (bone).

Notable exceptions exist including the malignant tumors, myelomas and lymphomas. Both are examples of malignant neoplasms.

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carcinoma vs sarcoma

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In the case of undifferentiated tumors, a distinction can be made between tumors of
epithelial origin and those of connective tissue/soft tissue origin. The former are referred to as carcinomas while the latter are termed sarcomas.

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-blastoma

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used to classify these malignant neoplasms difficult to classify histologicallyand include those of the
neuroendocrine system comprising cells that store biogenic amines in granules

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examples of blastomas (3)

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neuroblastoma (sympathetic neurons), retinoblastoma (embryonal retina) and
myoblastoma (muscle tissue).

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leukemia definition

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cancer of the cells in the blood, usually involves the over production of
leukocytes by two to three orders of magnitude

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proliferation- what is it? (2 steps)

how to regulate this (2)

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1) DNA synth and mitosis to produce new cells
2)cell differentiation (produce specialized cells)

growth factor and inhibitor

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stage of cell cycle where cells are committed to replication (2)

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G1/S derp** most important

G2/M

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growth factors/inhibitors in cancer

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become unbalanced with cancer (controlled production is broken) = increase GF, GF receptors which promotes transition to G1/S and G2/M phases

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biochemical basis of cancer (things that cause it) (4)

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1) mutation
2) chemicals
3) oncogenic viruses
4) altered gene expression

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2 steps that cancer requires to proceed

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both initiation (mutation) and then promotion

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timeline of cancers (5 steps)

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1) initial mutations
2) promotion (typically via chemicals)
3) small benign tumor
4) primary malignant tumor
5) cell breaks off and metastasizes

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promoters- what is they

3 examples

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promote cancer but not genotoxic alone

estrogens
phobalt 13 acetate
pesticides

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chemical structure that cause cancer and how

example of one and how it works

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soot causing scrotal cancer (poly aromatic ring)
alkylates DNA causes single base mutations

key here is POLYAROMATIC RING

benzo(a)pyrene- reactive epoxide attacks guanines

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ionizing radiation

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radon- iowa highest whatever- causes lung cancer
CT scans
etc.

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cancer chemical/environmental causes- (5)

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ionizing radiation
radon
hydrocarbons
UV light
aflatoxin

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aflatoxin- what is it

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carcinogen assoc. with liver cancer
in burnt proteins (peanuts, rice, bbq)

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oncogenic virus mechanism

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virus inserts itself into host genome then make proteins that interact with tumor suppressors

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things to take into consideration when evaluating how to treat a cancer (3)

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stage
type
location

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CANCER THERAPY methods (4)

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surgery
radiation therapy
Immunologic Therapy
Chemotherapy

often used in combo DERRRR

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shortcomings of chemo (3)

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1) less useful for large tumors (not well perfused in middle which is where the stem cells are)
2) Lack of selectivity
3) cytotoxic

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surgery (2)

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must be localized tumor
must be early detection to work

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mechanism of radiation therapy

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usually localized
causes dmg through ROS generation in cancer cells (x rays) to induce death

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immuno therapies for cancer

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boost lvls of lymphocytes (T/B cells)- by giving pt interferons

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chemotherapy types

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conventional or
targeted therapy kinda sucks

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chemo successes (3)

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1) early detection increases success?
2) testicular cancer treated with cisplatin
3) hodgkins disease much increased survival

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mustard structure

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---

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2 problems of targeted cancer therapy

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1) works only for small populations due to COST
2) mutations in cancer cells can screw up the whole treatment

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nitrogen mustards (6)

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mechlorethamine
Cyclophosphamide, ifosfamide, chlorambucil, estrantustine phosphate, and melphalan

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MoA of nitrogen mustards

phase affected (2)

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alkylates N7 on guanine of DNA forming monoadducts or guanine-guanine links

this leads to DNA instability and breaks

G1/S phase

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mechlorethamine- half life and route

mechanisms (chemically what is happening)
targets

Back 31

IV
very short half life

forms aziridine** which makes it susceptible to nucleophilic attack, alkylating guanine (N7)

Other sites on the DNA bases (guanine, adenine, thymine or
cytosine) or the phosphate oxygens of the DNA backbone may also be alkylated.

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selectivity of mustards- how?

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cancer cells proliferate very quickly and can't repair DNA as well as normal cells

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"other" alkylating agents (5)

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thiotepa
and busulfan and the nitrosoureas, carmustine and lomustine.

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melphalan structure

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phenylanaline mustard

also known as L-phenylalanine mustard or L-PAM, is a nitrogen mustard
chemically linked to a natural amino acid

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compare cyclophosphamide to other nitrogen moostards- nucleophilicity, formation of aziridine and what this means for PK, route, activation

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nucleophilicity of the mustard nitrogen is substantially reduced through an amide-like phosphoramide linkage.

As a result, cyclophosphamide is less likely to form an
aziridinium ion than are the alkyl-substituted nitrogen mustards. (more stable/better PK)

Cyclophosphamide is a
pro-drug.

Cyclophosphamide is well absorbed orally.

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cyclophosphamide metabolized by what, to what 2 things

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p450

phosphoramide mustard + crolein??

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ifosfamide- sar, metabolism

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analogue of cyclophosphamide that is also related in structure to the
nitrogen mustards except that the two chloroethyl arms are not attached to the same nitrogen.

Metabolic activation catalyzed by CYP45O enzymes is required for cytotoxic
activity.

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Estramustine- made from, SAR, route (and anything that happens during absorption)

Back 38

estradiol

The alkylating moiety is not a true mustard in that the nitrogen atom is acylated as part of
the carbamate functionality (carbamate has less e- withdrawing action than amide)

After oral administration, estramustine phosphate is rapidly
dephosphorylated during absorption.

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chlorambucil- SAR, absorption

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similar to melphalan but...not phenylalanine. An alternative approach to reducing the reactivity of alkyl nitrogen mustards is to attach an aromatic group to the nitrogen atom of the mustard, as in the drug chiorambucil.

It is absorbed orally

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chlorambucil metabolism

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undergoes metabolism in the liver to form phenylacetic acid mustard
as the major metabolite. The metabolite retains the nitrogen mustard moiety and shows
antineoplastic activity.

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carbamate

Back 41

O=N--O

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bisulfan- MoA, sar, solubility, route

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non mustard alkylating agent (NO aziridine formation)

sulfonic acid ester that is an electrophile with methane sulfonic acid (mesylate) acting as a leaving group.

It is a neutral molecule with poor water solubility

oral tablet

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thiotepta SAR/MoA

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aziridine-containing drug. At acidic pH (cancer cells = more acidic), the aziridine group is protonated
to provide a reactive aziridinium ion that is known to alkylate DNA

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thiotepta metabolism

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Metabolic desulfuration of thiotepa leads to a toxic metabolite, TEPA (triethylenephosphoramide).

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procarbazine MoA (2) specify where alklyaton occurs

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oxidized/isomerized to ROS and methylhydrazine

Methyl hydrazine
has been shown to methylate RNA and DNA. In DNA, methylation occurs on the C-8
position of guanine.

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procarbazine AE

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Procarbazine inhibits enzymes involved in alcohol metabolism and
catecholamine metabolism. Patients taking procarbazine may experience Antabuse
(disulfuram)-like effects with ethyl alcohol intake

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procarbazine DIs (3) and why

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Monoamine oxidase is inhibited by
procarbazine. Drug interactions with procarbazine and sympathomimetic drugs, tricycic
antidepressant agents, and other drugs and food high in tyramine content are possible

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dacarbazine- what is it, activation, route, MoA (2) make mention of the activte metabolite

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Dacarbazine is a dimethyl triazenyl imidiazole carboxamide (DTIC) (non mustard alkylating).

DTIG appears to be
metabolically bioactivated through a series of reactions involving CYP45O.

Initial demethylation to MTIC is followed by formation of diazomethane, a potent methylating agent.

Diazomethane in turn is capable of methylating the N-7 position of guanine.

Dacarbazine must be administered intravenously.

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temozolamide- what is it, indication, route, MoA

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non mustard alkylating agent

pro-drug which is nonenzymaticly converted into MTIC which then
alkylates DNA in a manor similar to that of DTIC.

Recently, the FDA has approved this
MTIC pro-drug for the treatment of brain tumors. It can be administered orally

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Nitrosoureas (2)

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carmustine

lomustine

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carmustine- melting point properties, solubility, aka?

Back 51

also known as BCNU, which is an acronym derived from the chemical
name, 1,3- bis(chloroethy]j-1-nitrosourea


highly lipophilic
and poorly soluble in water. (crosses BBB)

low melting solid. As carmustine decomposes, the
melting point drops such that partially degraded preparations may be in a liquid form at
room temperature

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carmustine- primary active metabolite

Back 52

vinyl cation- highly potent alkylating agent

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lomustine- aka, compare to carmustine

Back 53

also known as CCNU (1-(2- chloroethyl)-3-cyclohexyl-l-nitrosourea), is a
nitrosourea antineoplastic agent with similar structure, solubility, and activity
characteristics to carmustine.

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purpose of aromatic ring on alkylating agent (mustards)

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e- withdrawing so slows formation of aziridine (better PK properties- won't react with everything)

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streptozocin- structure/sar, how it relates to solubility (compare to other nitrosos), major AE shown in studies, class

Back 55

glucosamine nitrosourea

composed of a combination of a glucopyranose amino sugar and a
nitrosourea.

The sugar moiety, existing in both anomeric forms, imparts good water
solubility as compared to the lipophilic nitrosourea antineoplastic agents.

streptozocin has long been known to produce a diabetes like
syndrome in animals.

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cisplatin structure and MoA (2) protein binding

Back 56

alkylates N7 of guanine too
platinum complex containing two ammonia molecules and two chloride
atoms in a cis- configuration

After a dose of cisplatin, most of the platinum becomes
tightly bound to plasma proteins including albumin, transferrin and gamma globulin.

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cisplatin- antidote and what kind of needle not to use

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Because cisplatin is highly protein bound, hemodialysis as an antidote started four hours
after overdosing has little effect. For administration of cisplatin intravenously, needles or
intravenous sets containing aluminum parts should not be used because cisplatin reacts
with aluminum resulting in a precipitate and a loss of potency

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carboplatin- structure, potency and solubility

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same as cisplatin except has cyclic ester

less potent but better water solubility (replaced Cl with water? aquation reaction occurs at a
slower rate than it does in the case of cisplatin which may explain why carboplatin is less
potent than cisplatin.)

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antimetabolite definition

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Antimetabolites are compounds that prevent the biosynthesis of normal cellular
metabolites.

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MoA of antimetabolites (4)

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1) inhibition of kinases,
2) inhibition of enzymes involved in pyrimidine biosynthesis,
3) incorporation into RNA or DNA and subsequently cause misreading,
or
4) inhibition of
DNA polymerase

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5-FU- how was it developed? (what did scientists notice)

Back 61

The development of this compound was based on the observation that some tumors
preferentially use uracil rather than orotic acid for pyrimidine biosynthesis

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pyramidine antimetabolites (3)

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5-FU
cytarabine
gemcitabine

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MoA of 5-FU- compare normal to 5-FU

Back 63

SUICIDE inhibitor of thymidylate synthetase (looks like dUMP but with fluoride)

TS SH attacks dUMP with methylene-THF (methylating cofactor- not important)
having F instead of H at crucial location means that TS cannot detach itself from the complex

END RESULT: can't make dTMP

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5-FU- active drug?

Back 64

In vivo, 5-FU must first be activated by conversion to 5-fluoro-2’-deoxyuridylic acid (5-
FdUMP).

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metabolism of 5-FU- and how this relates to its 3 (4)

Back 65

inactivated or
can be phosphorylated and incorporated into RNA
or
converted to 5-FdUMP the thymidylate inhibitor
or
5-FdUMP can be +P and incorporated into DNA

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Cytarabine- sar (2), category, activation

Back 66

has OH that points up (in its endogenous analog it points down)

analog of cytidine (it is a cytosine arabinoside rather than ribose)

basically a pyrimidine antimetabolite in which the sugar has been
modified. It must be converted into monophosphate and then its triphosphate derivate.

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cytarabine- solubility, routes (3)

Back 67

water soluble sterile powder for intravenous, intrathecal, and
subcutaneous use.

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gemcitabine- sar, activation

Back 68

molecule bears two fluorines in
place of the hydrogen and hydroxyl nonnally present on C-2' of the sugar oup of cytosine

also needs to be activated like cytarabine to triphosphate (deoxycytidine kinase)

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purine antimetabolite moa (general)

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inhibits de novo synthesis of purines derp

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purine antimetabolites (4)

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6-mercaptouprine
6-thioguanine
cladribine
fludarabine

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enzyme that activates 6-mercaptopurine (and 6-thioguanine)

what is 6-mercapto's active form

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HGPRT
converts mercapto into 6-methyl thioinosate (basically phosphorylates it and puts a sugar on it)

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6 mercaptopurine metabolism (2)
absorption

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metabolized by xanthine oxidase
extensively metabolized in first pass

erratic absorption - has oral form tho

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6-thioguanine Moa

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An antimetabolite structurally related to 6-MP is 6-thioguanine (6-TG). Generally, 6-TG
parallels the activity of 6-MP.

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Fludarabine phosphate- structural relationship, sar, category

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purine antimetabolite that is structurally related to adenosine
and embodies both purine ring and sugar modifications (sugar points up not down)

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fludarabine vs. cladribine structure

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flu has fluoride and a flipped OH on sugar
cla has chloride...and no second OH group on sugar

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folate pathway

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pteridine-->dihydrofolate--(DHFR)-->THF

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MoA of methotrexate (2)

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directly inhibits DHFR- causes buildup of DHF which indirectly inhibits thymidylate synthetase, which inhibits DNA synth

also inhibits purine synth