New Analogs of Methotrexate in Cancer and Arthritis

Abstract

Abstract: Aminopterin and its N10-methyl analog; methotrexate, were synthesized in the late 1940s and methotrexate was subsequently incorporated into clinical use as an antitumor agent in the mid-1950s. In more recent years methotrexate has also become accepted as an effective agent for treatment of rheumatoid arthritis. Structure-activity studies have been ongoing over the past 40 years in an effort to develop a safer and more effective version of this powerful antifolate. Early work featured replacement of nitrogen atoms at various positions in the pterin ring, substitution about the phenyl ring in the side chain and alteration in the glutamic acid subunit. These studies shed considerable light on structural requirements for antitumor activity. However, new agents with serious potential for clinical introduction were not encountered until structural modification of the region bridging the pterin and benzoyl glutamate side chain took place. A series of 10-substituted-10-deazaaminopterin analogs was investigated and found to have activity superior to methotrexate in several tumor models in vivo. There was in vitro evidence for facilitated transport into tumor cells versus sensitive host tissue cells and increased polyglutamylation within the tumor cells such that a selective accumulation was achieved in tumor tissue. 10-Ethyl-10-deazaaminopterin (Edatrexate) was found to be clinically effective against lung and breast solid tumors. Our laboratories have continued to pursue structural modifications of 10-deaza, 5,10-dideaza and 8,10-dideazaaminopterins in an effort to improve upon the efficacy of edatrexate. Additional variation has been made in the "bridge region" and various heterocyclic rings have been introduced in place of the side chain phenyl ring. These modifications have resulted in additional new antitumor agents and compounds with activity exceeding that of methotrexate in rheumatoid arthritis.