Synthesis, mechanism of action, and biological evaluation of mitosenes

Abstract

Mitosenes of both the pyrrolo- and pyrido[1,2-a]indole type have been prepared via modification of these heterotricyclic compounds. Several mitosenes have been studied for their reactions with nucleophiles under reductive conditions. The results of these experiments show that the biological activity of mitosenes is based on the mechanism of bioreductive activation. When both leaving groups at C-1 and C-10 in the mitosene are the same, the nucleophile preferably adds to C-10 under reductive conditions. All mitosenes were studied for their biological activities in vitro against L1210, WiDr, and A204. On the basis of these results a selection of three mitosenes was made for a more detailed biological evaluation. Several tumor model systems were used, viz. P388, human tumor xenografts, MAC 13, and MAC 16. The results of these studies show that mitosenes have a more limited range of activities than mitomycin C. Surprisingly, the in vivo activities of mitosene diol 8b and mitosene diacetate 10b against the gastric human tumor xenograft GXF 97 were very high and comparable with that of mitomycin C.

Synthesis of Pyrido[1,2-a]indole Malonates and Amines through Aryne Annulation

“…6 Another series of compounds known as metosenes have shown significant antitumor activity. 7 However, the fully aromatic pyridoindole core has been mentioned in the literature only briefly, mainly due to the challenges in the preparation of this system. 8 Recent efforts, as shown herein, have focused on utilizing the nucleophilic nature of carefully designed pyridines for the synthesis of pyrido[1,2- a ]indoles.…”

Benzyne-mediated rearrangement of 3-(2-pyridyl)-1,2,4-triazines into 10-(1H-1,2,3-triazol-1-yl)pyrido[1,2-a]indoles

“…In summary, a non-trivial method for the synthesis of 10-(1H-1,2,3-triazol-1-yl)pyrido[1,2-a]indoles 3 has been reported. Pyrido[1,2-a]indoles are important in terms of their biological activity, in particular, cytostatic, 16 antiviral, 17 antitumor, 18 etc. The preparation of these compounds by other synthetic approaches, 19 including reactions with arynes, 20 is still rare.…”

Synthesis and Activity of Novel 5‐Substituted Pyrrolo[2,3‐d]pyrimidine Analogues as pp60c‐Src Tyrosine Kinase Inhibitors

“…Although several methods are available for reducing a cyano group to aldehyde [32,33], in this study, the cyano group was converted to aldehyde with DIBAL reduction with some modifications compared to the method reported in the literature [34]. In brief, among the tested conditions, the best one was the reaction carried out in methylene chloride at 08C; it resulted in the intermediate 5 [35].…”