YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Synthesis of Dihydropyrrole[3,4-f]quinazoline Antifolates and Their Antitumor Activity In Vitro

Dihydropyrrolo[3,4-f]quinazoline 엽산길항제의 합성 및 In Vitro 항암활성

  • Baek, Du-Jong (Department of Chemistry, College of Natural Sciences, Sangmyung University)
  • 백두종 (상명대학교 자연과학대학 화학과)
  • Published : 2006.08.31
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Abstract

Classical dihydropyrrole[3,4-f]quinazoline antifolates 7,8 and 9, in which the tricyclic ring is structurally similar to the pteridine ring of $CH_2-THF(1)$, the cofactor of thymidylate synthase (TS), were synthesized, and their in vitro antitumor activity was evaluated by measuring the cell growth inhibitory activity against cancer cell lines. The target compounds were cytotoxic against CCRF-CEM, human T-cell acute lymphoblastic leukemia, with the cell growth inhibitory activity $(IC_{50})$ of $0.8{\sim}8.3\;{\mu}M$. Among the three compounds, 3-amino analog 7 was 10- and 3.5-fold more cytotoxic compared to the 3-methyl analogs 8 and 9, and its cytotoxicity was similar to that of the reference compound with the $IC_{50}$ value of $0.83\;{\mu}M$. This result was supposed as the consequence of the fact that dihydropyrroloquinazolinone ring with amino group was able to bind well in the active site of TS. In the case of 3-methyl analogs, analog 9, which has two-carbon bridge between the dihydropyrroloquinazolinone ring and benzoyl-L-glutamic acid, was 3-times more potent in cytotoxicity than analog 8 which has one-carbon bridge, and this result indicates that the distance and conformational orientation of the benzoyl-L-glutamic acid moiety with respect to the tricyclic ring may also be a crucial determinant of cell growth inhibitory activity.

Keywords

References

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