Compounds Related to Methotrexate

TWO FUSED SIX-MEMBERED RINGS 15.3.1. Compounds Related to Methotrexate 

The pivotal role of folates in purine synthesis and consequently cell growth has been addressed earlier, as has the use of folate antagonists as cytotoxic agents. 

Methotrexate (53-6), one of the first modified pteridines investigated as a folate antagonist, is still used quite extensively in the chemotherapy of cancer and to a minor extent in other indications calling for cytotoxic agents. 

The synthesis of the analogue in which one of the pteridine nitrogen atoms is omitted starts with the reaction of aminopyrimidone (54-1) with 2-bromomalonalde-hyde (54-2). This condensation may be envisoned as involving an initial condensation 

Yet another cytotoxic agent that lacks the glutamate side chain illustrates the breadth of the SAR in this series. It is of note that the three nitrogen atoms in the fused six-membered ring system are disposed so as to form a pyridopyrazine rather than a pyrimidopyrimidine, as in piritrexim. The observation that this agent also inhibits tubulin may play an additional role in its activity. Nucleophylic aromatic 

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