Reductive activation of potential antitumor mitosene compounds

Abstract

The reductive activation of mitosene compounds was studied with cyclic voltammetry and HPLC analysis. Reduction of mitosenes, possessing good leaving groups at C-1 and C-10, was shown to result in loss of these groups at pH 7.0 and pH 6.0. The loss of leaving groups from mitosenes occurred faster at lower pH. Mitosenes without good leaving groups were found to be stable upon reduction. In the presence of acetoxy groups at C-1 and C-10, the C-10 site is the most reactive site upon reductive activation. This is opposite to the case of mitomycin C, where the C-1 site is the first to react upon reduction. At pH 6.0 without reduction, acid degradation also caused the loss of leaving groups of mitosenes, although at a very slow rate. In contrast to reductive activation, upon acid degradation of a diacetoxymitosene the C-1 group appeared to be lost faster. Electrochemical as well as dithionite reduction of a bifunctional (diacetoxy) mitosene compound in the presence of calf thymus DNA at pH 5.5 resulted in the formation of DNA interstrand cross-links. Depending on activation method, this diacetoxymitosene was at least as efficient in DNA cross-linking as mitomycin C under comparable conditions.

Semi-synthesis and antitumor activity of 6-isomers of 5, 8-O-dimethyl acylshikonin derivatives

“…Compound 5a, 5f, 5p, 5r exhibited 2e9-fold more active and selective toward MDA-MB-231 and MCF-7 cell lines than the corresponding isomers 6ae6d, and the tendency was in good accordance with the relationship of 6-isomers and 2-isomers of DMNQ analogues against L1210 cell [7,8]. The greater activities of 6-isomers than 2-isomers were due to the introduction of the same side chain with an ester group into different positions of 6-and 2-isomers and the exposure of quinone moiety as a Michael acceptor to cellular nucleophiles [9,18]. Although compound 6ae6d were shown to have slightly more effective on K562, CNE and HCT-15 cell lines than those of the corresponding 6-isomers except compound 6a against K562, on the whole the inhibitory activities to these cell lines decreased significantly than the lead compound shikonin.…”

Mitomycinoid Alkaloids: Mechanism of Action, Biosynthesis, Total Syntheses, and Synthetic Approaches

“…[132] Compounds of the type depicted in Figure 4 were shown to display antitumor activity which correlated primarily with lipophilicity. [133] The bis-acetoxy compound named WV15 (R 1 = Me, R 2 =R 3 =OCOCH 3 , n=1) presents a different pattern of reactivity from that of MMC as inferred from the structures of two dimeric WV15-DNA monoadducts in which the bond formed is between the mitosene C-10 and deoxyguanosine N-2 atoms. [134] …”

Synthesis‐Enabled Probing of Mitosene Structural Space Leads to Improved IC50 over Mitomycin C

“…We reasoned that the strained ring could behave like a Michael‐type receptor and react with another base of the same DNA molecule, thereby realizing a second alkylation. It needs to be pointed out that the order of these two alkylation events could be reversed 11. Nevertheless, the introduction of a new alkylation mechanism via the cyclopropane intermediate B , while maintaining the reductive initiation, would make hitherto unexplored chemical space around the MMC/mitosene skeleton available for addressing the issues associated with MMC.…”