Initiation of DNA strand cleavage by 1,2,4-benzotriazine 1,4-dioxide antitumor agents: mechanistic insight from studies of 3-methyl-1,2,4-benzotriazine 1,4-dioxide.
Initiation of DNA strand cleavage by 1,2,4-benzotriazine 1,4-dioxide antitumor agents: mechanistic insight from studies of 3-methyl-1,2,4-benzotriazine 1,4-dioxide.
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DOI：
10.1021/ja8049645
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发表时间：
2009-01-28
影响因子：
15
通讯作者：
Gates, Kent S.
中科院分区：
文献类型：
--
作者：
Junnotula, Venkatraman;Sarkar, Ujjal;Sinha, Sarmistha;Gates, Kent S.
抗肿瘤剂3-氨基-1，2，4-苯并三嗪1，4-二氧化物（替拉扎明，TPZ，1）通过其选择性损伤实体瘤内缺氧细胞中DNA的能力获得药用活性。这通过TPZ的单电子酶促还原产生氧敏感性药物自由基（2）而发生，其导致在缺氧条件下氧化产生的DNA损伤。两种可能的机制已被认为是占氧化产生的DNA损伤TPZ。首先，2中的N-OH键的均裂可能产生众所周知的DNA损伤剂羟基自由基。或者，有人认为，从2中除去水会产生苯并三嗪基自由基（4），作为最终的DNA损伤物质。在本文所述的研究中，TPZ类似物3-甲基-1，2，4-苯并三嗪1，4-二氧化物（5）被用作探索这类新型抗肿瘤药物中DNA损伤机制的工具。最初，它被证明5导致氧化还原激活，缺氧选择性氧化的DNA和小的有机底物的方式是完全类似于TPZ。这表明5和TPZ通过相同的化学机制损伤DNA。重要的是，5中的甲基取代基提供了一种评估推定的苯并三嗪基中间体7是否在单电子还原后产生的手段。两个互补的同位素标记实验提供了证据，反对形成的benzotriazinyl自由基中间体。相反，涉及从活化的药物自由基中间体释放羟基自由基的机制可以解释这类抗肿瘤候选药物的DNA切割特性。
The antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ, 1) gains medicinal activity through its ability to selectively damage DNA in the hypoxic cells found inside solid tumors. This occurs via one-electron enzymatic reduction of TPZ to yield an oxygen-sensitive drug radical (2) that leads to oxidatively generated DNA damage under hypoxic conditions. Two possible mechanisms have been considered to account for oxidatively generated DNA damage by TPZ. First, homolysis of the N–OH bond in 2 may yield the well known DNA-damaging agent, hydroxyl radical. Alternatively, it has been suggested that elimination of water from 2 generates a benzotriazinyl radical (4) as the ultimate DNA-damaging species. In the studies described here, the TPZ analogue 3-methyl-1,2,4-benzotriazine 1,4-dioxide (5) was employed as a tool to probe the mechanism of DNA damage within this new class of antitumor drugs. Initially, it was demonstrated that 5 causes redox-activated, hypoxia-selective oxidation of DNA and small organic substrates in a manner that is completely analogous to TPZ. This suggests that 5 and TPZ damage DNA by the same chemical mechanism. Importantly, the methyl substituent in 5 provides a means for assessing whether the putative benzotriazinyl intermediate 7 is generated following one-electron reduction. Two complementary isotopic labeling experiments provide evidence against the formation of the benzotriazinyl radical intermediate. Rather, a mechanism involving the release of hydroxyl radical from the activated drug radical intermediates can explain the DNA-cleaving properties of this class of antitumor drug candidates.
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