Ecteinascidin 743:  A Minor Groove Alkylator That Bends DNA toward the Major Groove

Abstract

The ecteinascidins (Ets), which are natural products derived from marine tunicates, exhibit potent antitumor activity. Of the numerous Ets isolated, Et 743 is presently being evaluated in phase II clinical trials. Et 743 binds in the minor groove of DNA and alkylates N2 of guanine. Although structurally similar to saframycin, which exhibits poor activity in cellular assays, Et 743 has shown good efficacy as an antitumor agent. In this study, DNA structural distortions induced by Et 743 were examined to provide insight into the molecular basis for the antitumor activity of Et 743. Electrophoretic mobility shifts of ligated oligomers containing site-directed adducts were used to examine the extent and direction of the Et 743-induced bend. Surprisingly, we find that Et 743 bends DNA toward the major groove, which is a unique feature among DNA-interactive agents that occupy the minor groove.

Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation

“…Exactly how ET-743 could affect interaction with other factors is an open question. However, Hurley and colleagues (11) have shown that ET-743 bends DNA toward the major groove, which is a unique feature among DNA-interactive agents that occupy the minor groove. One could envision how the interaction of ET-743 with DNA could alter local promoter architecture, preventing functional complex formation or inhibiting interactions with other components of the transcriptional machinery.…”

“…Preclinical studies have shown that ET-743 is toxic to most tumor cell lines in the nanomolar to subnanomolar range; indeed, antitumor effects were observed in phase I trials with concentrations of less than 2 mg͞m 2 body weight. Although ET-743 has been shown to bend and alkylate DNA in the minor groove (11,12), cause microtuThis paper was submitted directly (Track II) to the PNAS office.…”

Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743

“…As a result, the minor groove is opened up and bended toward the major groove (19). The direction of bending is a novel feature among DNA minor groove-interactive agents, making ET-743 unique.…”

Organismos marinhos como fonte de novos fármacos: histórico & perspectivas

“…Esta molécula liga-se à guanina em sequên-cias específicas de bases nas fendas menores da dupla hélice, causando uma dobra nas fitas de DNA. 45,46 Este dobramento tem diversas consequências celulares que são refletidas na desorganização do citoesqueleto, bloqueio da divisão celular e interferência no reconhecimento e ligação normal de fatores de transcrição ou proteínas ligantes ao DNA, causando ativação ou inibição de determinados genes. 47,48 A inibição da transcrição do gene MDR1 é um dos principais e mais relevantes efeitos desta substância, sendo este gene responsável pela produção de glicoproteína-P, uma proteína que realiza o bombeamento de diversos quimioterápicos para fora das células e pode estar superexpressa em células tumorais.…”