Methotrexate

Structure of Methotrexate

Methotrexate is a folate analog with the following structural features:

• Pteridine Ring: Core structure similar to folic acid.

• Glutamate Residues: Multiple glutamate moieties attached to the pteridine ring.

• Chemical Formula: C₂⁰H₂⁷N₇O₇

Structure of Methotrexate

Mode of Action

Methotrexate acts as an antimetabolite and antifolate by:

• Inhibition of Dihydrofolate Reductase (DHFR): Prevents the conversion of dihydrofolate to tetrahydrofolate, essential for DNA synthesis.

• Inhibition of Thymidylate Synthase: Reduces dTMP synthesis, hindering DNA replication.

• Induction of Apoptosis: Causes cytotoxicity in rapidly dividing cells.

Uses

1. Acute Lymphoblastic Leukemia (ALL): As part of multi-agent chemotherapy.

2. Breast Cancer: In certain treatment protocols.

3. Ovarian Cancer: Alongside other chemotherapeutic agents.

4. Rheumatoid Arthritis: As a disease-modifying antirheumatic drug (DMARD).

5. Psoriasis: In severe cases unresponsive to other treatments.

6. Ectopic Pregnancy: To terminate non-viable pregnancies.

Structure-Activity Relationship (SAR)

• Pteridine Core: Essential for binding to DHFR and other target enzymes.

• Glutamate Residues: Enhance cellular uptake via folate transporters and increase drug retention within cells.

• Carbonyl Groups: Participate in hydrogen bonding, enhancing binding affinity to target enzymes.

• Substitution Patterns: Modifications on the pteridine ring can affect potency and selectivity.

Synthesis

Methotrexate can be synthesized through the following steps:

• Starting Material: Pteridine derivatives.

• Attachment of Glutamate Residues: Sequential addition of glutamate moieties to the pteridine core.

• Protection and Deprotection Steps: To ensure selective functionalization.

• Purification: Isolation of Methotrexate through crystallization and recrystallization processes.

Synthetic Route Overview:

• Pteridine Core → Glutamate Attachment → Methotrexate