Synthesis and Biological Activity of New Class of Dioxygenated Anticancer Agents

Maria   Dolors   Pujol; Manel      Romero; Isabel      Sanchez

doi:10.2174/1568011053765930

Abstract

This paper describes extensive research on the activity of more of 100 cytotoxic compounds containing an oxygenated ring in their structure and isolated from natural plants or prepared by semisynthesis or synthesis from available intermediates. Anticancer drugs have been classified according to the chemical structure of the natural products that are considered to lead the series. The origin and mechanism of action involved in each case have been considered. This new family of natural, semisynthetic and synthetic products includes compounds with interesting antitumor activity such as podophyllotoxin derivatives, NK-611 (15), TOP-53 (16), NPF (24) and Tafluposide (28); camptothecin analogs such as 45 with a considerable cytotoxicity against β-cell chronic lymphocytic leukemia (CLL), and 52 (new piperazinyl- CPT analog). New dioxygenated ellipticine analogs showed more activity and stability than the natural pattern when the structure incorporated a lactone function instead of the pyridine ring. In the acridine series the new tetracyclic derivatives 75 and 76 containing ethylenedioxy groups at the 2- and 3-positions of the acridine system exhibited the same activity as m-AMSA in vivo against murine P-388 leukemia. Other isolated compounds containing a dioxygenated ring in their structure such as 100 and 101 showed antitumor activities related to kinase inhibition, and are attractive candidates for development of new synthetic antitumor agents.

Keywords: chemotherapeutic agents, podophyllotoxin, dna intercalators, quinolidizine analogs, topoisomerase II, tafluposide, butyrolactones, camptothecin, antitumor activity, human colon xenografts