Synthesis and antiproliferative activities of isoindigo and azaisoindigo derivatives

Abstract

In the course of structure-activity relationship studies, diversely substituted 1-(beta- d-acetylatedglucopyranosyl)isoindigo derivatives were prepared from indolines. New 7'-azaisoindigo analogues were also synthesized by coupling a glycosylated isatine and a 7-azaindolin-2-one derivative. Compounds containing a 7'-azaisoindigo framework have never been described before. To get an insight into the substitution pattern required for the best biological potencies, their antiproliferative activities were evaluated toward a human buccal carcinoma cell line (KB) and two human myeloid leukaemia cell lines (K562, HL60).

Synthesis, kinase inhibitory potencies and in vitro antiproliferative activity of isoindigo and 7′-azaisoindigo derivatives substituted by Sonogashira cross-coupling

“…The alkynyl side chains were introduced in the 5′-position of the isoindigo or 7′-azaisoindigo framework by Sonogashira coupling using Pd(PPh 3 ) 4 in acetonitrile in the presence of CuI and Et 3 N. In these conditions, compounds 5 and 6, brominated or not and bearing a Cbz-protected aminopropyl side chain at the 5′-position were obtained in respectively 24% and 33% yields. Compounds 7 and 8 were obtained from 3 or 4 in 14 and 41% yield respectively, using the same catalytic conditions in the presence of but-3-yn-1-ol.…”

“…In these latter catalytic conditions, none of the expected coupling products was observed. As we had already described the preparation of the 7-aza-5-bromoindolin-2-one 9 [4], in the aza series, the Sonogashira cross-coupling reactions were first attempted with brominated intermediates. Compound 11 was prepared in 51% yield by coupling glycosylated isatin 2 and 7-aza-5-bromoindolin-2-one 9 in acidic conditions as already described for the synthesis of the mono-brominated analogue 10 [4] (Scheme 2).…”

“…Finally, the coupling reaction performed between the iodo derivatives 13, 14 and the Cbz-protected propargylamine with Pd(PPh 3 ) 4 in acetonitrile in the presence of CuI, Et 3 N led to the attempted products 15 and 16 in respectively 39 and 45% yields (Scheme 3). Compound 17 was obtained from 13 and but-3-yn-1-ol in 25% yield by using the same reaction conditions.…”

“…In our previous work, we have described the synthesis of 5′-iodoglycosyl-isoindigo 3 by coupling in acidic conditions of the glycosylated isatin 1 with 5-iodoindolin-2-one [4]. The brominated analogue 4 was prepared in 68% yield, from 5-bromo glycosylated isatine 2, using the same procedure (Scheme 1).…”

“…We have reported, in previous papers, the synthesis and biological activities of isoindigo derivatives (indirubin isomers possessing two indolin-2-one moieties) bearing a sugar residue attached to one of the aromatic nitrogens and diversely substituted on the aromatic rings at the 5-, 6-and/or 5′-positions [1], [2], [3] and [4]. 7′-Azaisoindigo analogues were also prepared to evaluate the influence of a 7-azaindolin-2-one moiety instead of an indolin-2-one part on the biological activities of these compounds [4]. The results obtained in these previous structure-activity relationship studies have shown that the pharmaceutical profile of this series could be optimized by substitutions of the upper oxindole moiety, bromination in the 5-position and the presence of acetyl groups on the sugar residue.…”