Works on 3 Reactions in Purine Biosynthesis 

Noncompetitive inhibitor of P-Rib-PP Synthetase(1/2)

Inhibits IMP Dehydrogenase (3)

Prodrug= HGPRT adds sugar

Active Species: 6-MPRP (R=H) & 6-TGRP (R=HN2)

Ki= 190 µM

Purine Biosynthesis 

Glutamine Analog

Blocks glutamine from binding

Stops FGAR to AIR reaction

Mixed inhibitor of both IMP DHase (IMP to XMP) and GMP Synthetase in GMP formation

Imidazole nucleoside

Inhibits IMP DHase (IMP to XMP) in GMP formation

Purine Biosynthesis 

Catalyzes the oxidation of IMP to XMP

in formation of Guanine (XMP to GMP)

Purine Biosynthesis 

Competitive inhibitor of DNA polymerase

Purine Analog (fake building block)

Antiviral

2'-OH in Beta position instead of Alpha

Destroyed by Adenosine Deaminase (ADA)

Give in combination with ADA inhibitor 

Removes amine from bases with addition of water to inactivate bases

Also inactivates Puine Analog Drugs!

Defiency in ADA: SCID= "Bubble Boy Syndrome" 

ADA inhibitor

NOT an ANTI-CANCER DRUG 

7 Membered Ring

Transistion-State Inhibitor

Give with Purine Analogs subject to ADA metabolism 

Purine Analog

X=F 

Fake Building Block

Good activity with CLL 

Subject to ADA metabolism = inactivation

Give with pentostatin 

Purine Analog

X=Cl

2'-deoxy

Subject to ADA metabolism

Give in combination with pentostatin 

pKa = 5.4

Amount in urine is a marker for purine metabolism 

Antihyperuricemia Agent

Inhibits Xanthine Oxidase (XO) to stop formation of Uric Acid

Indication: Gout 

Condition where serum urate level exceeds the serum solubility of monosodium urate

Sodium urate > 7mg/dL

Causes Gout 

Emergency purine synthesis of building blocks

Guanine = HGPRTase

Adenosine = APRTase

with PRPP 

Puts sugar and base together 

PRPP to PRA (1st Rate Limiting Step)

PRA multiple steps to IMP (Major Precursor)

IMP to either AMP or GMP (mono-phospate)

AMP/GMP to dATP/dGTP (diphosphate) to DNA 

Too much mono-phosphate base

1. GMP deaminated to Xanthine to Uric Acid by Xanthine Oxidase (XO)
2. AMP deaminated to Hypoxanthine to Xanthine to Uric Acid (both by XO) 

PNP cleaves glucosidic bond to split base and sugar

Xanthine Oxidase breaks down bases to form Uric Acid

Thymidine

Cytosine 

Simpler

UMP = major precursor 

Adenosine

Guanine

SALVAGE PATHWAY

IMP Major Precursor

2 Rate Limiting Reactions (Feedback Inhibition)

1. First Step: Rib-5-P to P-Rib-PP with ATP to AMP
2. FAICAR to IMP with H20

Pyrimidine Biosynthesis 

Transition-State Inhibitor

Inhibits Aspartate Carbamoyltransferase 

Carbonic Acid to Carbamoyl Aspartate

(Glutamine Required in Reaction)

Replaces carbamoyl phosphate's oxygen with methylene 

Vitamin B9

Required as a precursor for coenzymes 

Can not make pteridine ring in vivo

Must get from diet 

Requires active transport

1. Pteridine
2. PABA (p-Aminobenzoic Acid)
3. Glutamic Acid

Coenzyme 

Dietary Folic Acid to DHFA (Dihydrofolic Acid) to THFA

Reduced by Dihydrofolate Reductase with NADPH

Converted to other cofactors...

N10-Formyl THFA (-CHO) Purine Biosynthesis

N5,10-Methylene THFA (-CH2-) Pyrimidine Bio.

Used as one-carbon transfer agents 

Precursor: UMP

Formed by Thymidylate Synthase which ADDS METHYL

Plus N5,N0-Methyline THFA (donates Carbon) then releases THFA (recycled)

*Acidic H on N5,N10 Methyline THFA allows cleavage (RXN WOULD NOT HAPPEN WITHOUT H) 

THFA to N5,N10-Methylene-THFA

Enzyme: trans-hydroxy methylase

Plus Serine (gives carbon) then releases Glycine

CRITICAL for TMP synthesis! 

Inhibitor of Thymidylate Synthase (UMP to TMP)

Irreversible Ternary Complex (F not a good leaving group)

Immobilizes Enzyme

PRODRUG

ACTIVE METABOLITE: FdUMP

5-FU with Phosphoribosyltransferase to FUMP to FUDP with Ribonucleotide Reductase (ONLY ACCEPTS MONOPHOS) to FdUDP to FdUMP

Inhibitor of Dihydrofolate Reductase

Good in Combo with 5-FU 

Calcium Salt of folinic acid

Aldehyde on N5 

NOT A ANTICANCER DRUG

Does NOT require reduction by DHFR

Helps protect normal cells from toxic effects of drugs (ex. MTX) 

Purine and Pyrimidine Biosynthesis

CELL CYCLE SPECIFIC at G1 to S Phase 

Inhibits Ribonucleotide reductase (ONLY ACCEPTS DIPHOSPHATES)

Stops all ribonucleotide-5'-phosphates to their 2'-deoxy analogs

Kills S phase of cell cycle 

Synergistic with radiation

Destroys a tyrosine radical 

Trigger "celluclar suicide"

TOXIC

NON-CELL PHASE SPECIFIC

Nitrogen Mustard

PRODRUG (activated by CYP 2B)

Forms both Acrolein (TOXIC) & ACTIVE Metabolite (Then forms 'Azirinium ion' = kills cancer cells)

OR Urinary metabolite INACTIVE (Inactivated more in normal cells = selectivity)

Cystine Analog 

Co-administer with cyclophosphamide to reduce the toxic effects of Acrolein

Acrolein is suceptable to Michael Addition which causes nephrotoxicity and neurotoxicity 

Dialkylators: crosslink DNA; depurination; miscoding and liking to a protein

Depurination leads to abasic site

(base and sugar detached)

"Sulfer Stripping": destroys Busulfan with -CH3SO3H (strong acid) 

Alkylating Agent

NON-CELL PHASE SPECIFIC 

CVNU (or CCNU) split to Isocyanate & Alkyl Diazohydroxide

Isocynate carbamoylated to form TOXIC products

Alkyl Diazo. decomposed to Carbonium Ion (potent alkylating species) & OH-

Prevent toxicity with a neutralized carbamate ester to stop isocyanate formation 

To treat or prevent infections from other cancer treatments

Inhibit DNA/RNA synthesis by intercalation 

NON-CELL PHASE SPECIFIC 

Daunorubicin (Daunomycin)

Doxorubicin (Adriamycin) tighter binding & higher ∆nw

1. Intercalation (Driving force = ability to push water out ∆nw) MINOR GROOVE
2. Radical Formation (superoxide: O2-•)

Fenton Reaction uses superoxide to form hydroxyl radicals (•OH) = chops DNA

3.  Formation of a ferric complex using Fe3+

Fenton Reaction form hydroxyl radical (•OH)

Antitumor Antibiotic 

Glycopeptide antibiotic

Causes single and double strand breaks 

Cleaves double strands selective at 5'-GC and 5'-GT site in MINOR goove (metal and O2 dependent)

Combination with chemotherapy for HNC, lymphomas, and testicular cancer

Metal binding region, intercalation region, linder region, sugar region 

Interfere with the body's chemical process

Disrupt DNA production 

CELL PHASE SPECIFIC at G1 to S Phase

'Onium' Intermediate (+ charge)

Blocks the effects of hormones on tumors

ex. Antiestrogens

Derived from plants which prevent cancer cells from dividing successfully

CELL CYCLE SPECIFIC at G2 to M Phase 

Guanine to Cytosine

- 3 H bonds 

Adenosine to Thymidine (uracil in RNA)

- 2 H bonds 

Drug inserted into DNA helix

No change to W/C base pairs 

ALWAYS 5' to 3'

Helicase: breacks double helix into single strands

ONLY TRIPHOSPHATE will be accepted

Polymerase: adds bases at replication fork 

REQUIRES 3 THINGS

1. Template
2. Building Blocks
3. TWO MG +2 IONS: keep phosphates stable 

Precursor for AMP and GMP

Require...

1. Glycine
2. CO2
3. Aspartic Acid
4. N10-Formyl-THF (from Folic Acid)
5. 2 Glutamine
6. N5,N10-Methenl-THF (from Folic Acid)