# Synthesis and Evaluation of Antitumor and Anti-Angiogenesis Activity of Pyrone- or Pyridone-Embedded Analogs of Cortistatin A

## 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.

## Key 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.