10.1021/jm980081y.s001
Aleem Gangjee
Aleem
Gangjee
Anup P. Vidwans
Anup P.
Vidwans
Anil Vasudevan
Anil
Vasudevan
Sherry F. Queener
Sherry F.
Queener
Roy L. Kisliuk
Roy L.
Kisliuk
Vivian Cody
Vivian
Cody
Ruming Li
Ruming
Li
Nikolai Galitsky
Nikolai
Galitsky
Joe R. Luft
Joe R.
Luft
Walter Pangborn
Walter
Pangborn
Structure-Based Design and Synthesis of Lipophilic 2,4-Diamino-6-Substituted
Quinazolines and Their Evaluation as Inhibitors of Dihydrofolate Reductases
and Potential Antitumor Agents
American Chemical Society
1998
analogue
Toxoplasma gondii dihydrofolate reductase
gondii cells
GI
culture
National Cancer Institute
tumor cells
diamino
regiospecific reductive amination
Potential Antitumor Agents
regiospecific reductive methylation
inhibitor
gondii DHFR inhibition
1998-08-12 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Structure-Based_Design_and_Synthesis_of_Lipophilic_2_4-Diamino-6-Substituted_Quinazolines_and_Their_Evaluation_as_Inhibitors_of_Dihydrofolate_Reductases_and_Potential_Antitumor_Agents/3683661
The synthesis and biological activities of 14 6-substituted 2,4-diaminoquinazolines are reported.
These compounds were designed to improve the cell penetration of a previously reported series
of 2,4-diamino-6-substituted-pyrido[2,3-<i>d</i>]pyrimidines which had shown significant potency and
remarkable selectivity for <i>Toxoplasma gondii</i> dihydrofolate reductase (DHFR), but had much
lower inhibitory effects on the growth of <i>T</i>. <i>gondii</i> cells in culture. The target N9−H analogues
were obtained via regiospecific reductive amination of the appropriate benzaldehydes with 2,4,6-triaminoquinazoline, which, in turn, was synthesized from 2,4-diamino-6-nitroquinazoline. The
N9−CH<sub>3</sub> analogues were synthesized via a regiospecific reductive methylation of the corresponding N9−H precursors. The compounds were evaluated as inhibitors of DHFR from
human, <i>Pneumocystis carinii</i>, <i>T</i>. <i>gondii</i>, rat liver, <i>Lactobacillus</i> <i>casei</i>, and <i>Escherichia</i> <i>coli</i>,
and selected analogues were evaluated as inhibitors of the growth of tumor cells in culture.
These analogues displayed potent <i>T</i>. <i>gondii</i> DHFR inhibition as well as inhibition of the growth
of <i>T</i>. <i>gondii</i> cells in culture. Further, selected analogues were potent inhibitors of the growth
of tumor cells in culture in the in vitro screening program of the National Cancer Institute
with GI<sub>50</sub>s in the nanomolar and subnanomolar range. Crystallographic data for the ternary
complex of hDHFR−NADPH and 2,4-diamino-6-[<i>N</i>-(2‘,5‘-dimethoxybenzyl)-<i>N</i>-methylamino]pyrido[2,3-<i>d</i>]pyrimidine, <b>1c</b>, reveal the first structural details for a reversed N9−C10 folate
bridge geometry as well as the first conformational details of a hybrid piritrexim−trimetrexate
analogue.