Recent Progress in Syntheses of 9-Membered Masked Enediyne Analogues and their DNA Cleaving Activities

Abstract

This account describes our design, syntheses and DNA cleaving activities of a series of 9-membered masked enediyne analogues 8, 9, 19, 30, 44, 46, 47, 48, 49, and 50. In the first part of this report, we describe the development of a new method for the construction of 9-membered enediyne structures of NCS 8 and kedarcidin-C1027 9. The method involves the transannular [2, 3] -Wittig rearrangement of the 12-membered cyclic ether to construct the highly strained 9-membered diyne. In the second part of this report, we describe the syntheses of the masked enediyne analogues of NCS 19 and kedarcidin-C1027 30 possessing trans-hydroxy groups at C (10) and C (11). Palladium-catalyzed ring-opening of the ene-oxides 27 and 34 was applied to the introduction of the trans relative stereochemistry at C (10) and C (11) for the attachment of DNA recognition elements. Phthalic acid serves as a suitable “trigger” to control the stability of the 9-membered diynes and to generate enediynes for the DNA cleaving experiment. Both 19 and 30 caused DNA cleavage with the formation of Form II and Form III. In the last part of this report, we describe the synthesis of the masked enediyne analogues 44, 46, 47, 48, 49, and 50 possessing the DNA intercalator of NCS and/or sugar moieties. DNA cleaving experiments of 44 showed that introduction of the DNA intercalators improved DNA cleaving activity about 10 fold compared with the corresponding alcohol 30. Introduction of sugar moieties to the masked enediyne was achieved via S-alkylation of a bromoacetate derivative with a sugar-containing thiol without the need for protection of the sugar moiety. DNA cleaving experiments showed that the masked enediyne analogues 46, 47, 48, 49, and 50 possessing sugar moieties induced sequence-selective DNA cleavage and that the simple sugars serve as a DNA recognition element for DNA cleavage.