Synthesis and Evaluation of Antitumor and Anti-Angiogenesis Activity of Pyrone- or Pyridone-Embedded Analogs of Cortistatin A
Yuri Fujimoto, Kanako Mizuno, Yuta Nakamura, Masayoshi Arai, Naoyuki Kotoku
TL;DR
Researchers created and tested simplified versions of a natural compound to find new antitumor agents that block blood vessel growth in cancer.
Contribution
A pyridone-embedded analog of cortistatin A was developed with potent anti-angiogenesis and antitumor activity.
Findings
Pyrone- or pyridone-based analogs of cortistatin A were synthesized and evaluated for antitumor activity.
Analog 19 showed strong inhibition of human endothelial cells with high selectivity and in vivo efficacy against sarcoma.
The compound outperformed natural products in growth inhibition and antitumor effects in mice.
Abstract
Simplified analogs of cortistatin A were synthesized and biologically evaluated to develop novel antitumor substances that target angiogenesis. To analyze the effect of substituents at positions corresponding to C-2 and/or C-4 of the A-ring, various pyrone- or pyridone-embedded analogs were designed and synthesized. Among the prepared analogs, the pyridone analog 19 bearing a methyl group at C-2 and a hydroxyl group at C-4 showed potent and selective growth inhibitory activity against human umbilical vein endothelial cells (HUVECs, IC50 = 0.001 µM, selective index over that against human epidermoid carcinoma KB3-1 cells = 6400), exceeding those of natural products. The analog 19 of oral administration exhibited excellent in vivo antitumor activity in mice subcutaneously inoculated with sarcoma S180 cells.
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Taxonomy
TopicsCancer Treatment and Pharmacology · Synthetic Organic Chemistry Methods · Oxidative Organic Chemistry Reactions