Conformational analysis of antineoplastic antifolates: the crystal structure of trimetrexate and the aminopterine derivative 4-[N-[(2,4-diamino-6-pteridinyl)methyl]amino]benzoic acid
- 1 October 1987
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 30 (10) , 1843-1848
- https://doi.org/10.1021/jm00393a027
Abstract
The crystal structures of trimetrexate (TMQ) (2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline) and 4-[N-[(2,4-diamino-6-pteridinyl)methyl[amino] benzoic acid (PMAB) were determined to examine their conformational features with respect to the enzyme-bound form of methotrexate (MTX). TMQ and MTX are antineoplastic drugs that act by inhibiting the enzyme dihydrofolate reductase. The molecular conformation of TMQ is extended with the trimethoxyanilino ring twisted 89.degree. from the quinazoline plane, and the molecular conformation of PMAB is completely planar. The geometry of the 2,4-diaminopteridine and 2,4-diaminoquinazoline rings are sensitive to protonation, and both TMQ and PMAB have geometries characteristics of a free base. TMQ crystallizes as a dimethyl sulfoxide hydrate. The quinazoline ring forms an antiparallel stacking arrangement in the lattice and forms a network of N .cntdot..cntdot..cntdot. O hydrogen bonds with the solvent molecules. In PMAB there are both pteridine-benzoic acid (N .cntdot..cntdot..cntdot. O) hydrogen bonds and pteridine-pteridine (N .cntdot..cntdot..cntdot. N) hydrogen bonds. Although the molecular conformation of TMQ and PMAB differ from enzyme-bound MTX, rotational energy barriers calculated using CAMSEQ indicate athat they can adopt a similar conformation to that seen for MTX complexed with dihydrofolate reductase. These energy calculations show that PMAB is quite flexible and further suggest that the 5-methyl in TMQ reduces its conformational flexibility in a different manner than the N(10)-methyl in MTX. These structural data also show that full geometry optimization and proper parameterization of electronic effects at N(10) are required to accurately represent antifolate conformational preferences for enzyme binding.This publication has 12 references indexed in Scilit:
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