Design, Synthesis, and Cytotoxic Evaluation of a New Series of 3-Substituted Spiro[(dihydropyrazine-2,5-dione)-6,3‘-(2‘,3‘-dihydrothieno[2,3-b]naphtho-4‘,9‘-dione)] Derivatives

Abstract

A series of 3-substituted spiro[(dihydropyrazine-2,5-dione)-6,3'-(2',3'-dihydrothieno[2,3-b]naphtho-4',9'-dione)] derivatives were prepared using an easy synthetic route via condensation of the 3-amino-3-(ethoxycarbonyl)-2,3-dihydrothieno[2,3-b]naphtho-4,9-dione system and amino acids followed by intramolecular lactamization. Amino acids containing alkyl and aryl, linear and cyclic, polar and apolar, and basic and acid residues were incorporated. Evaluation of these analogues against the MCF-7 human breast carcinoma and SW 620 human colon carcinoma cell lines revealed, for the 3S,3'R isomers derived from Pro (7a), Cys (11a), and Met (12a) and the 3R,3'S isomer derived from D-Pro (7c), a cytotoxic potency comparable to or greater than that of doxorubicin. Some of these selected analogues were potent cytotoxic agents in several other sensible and resistant human solid tumor cell lines and may be able to circumvent the multiple-drug-resistance mechanism. In particular, only a partial cross-resistance to the compounds 7, 11, and 12 was observed in selected tumor cell sublines known to be resistant to doxorubicin (MCF-7/Dx and A2780/Dx), whereas a very low level of cross-resistance to compounds 7 and 11 was found in a tumor cell subline selected for resistance to cisplatin (A2780/DDP). In addition, the topoisomerase II inhibition activity and DNA-binding properties were investigated.

Design and synthesis of spirotryprostatin-inspired diketopiperazine systems from prolyl spirooxoindolethiazolidine derivatives

“…Previous work in our group on the synthesis of quinone-based cytotoxic agents, had confirmed that the incorporation of an indolizidindione moiety is an effective approach to devise new compounds with potential antitumor activity. 11 In this paper, we report a full account of our efforts towards the synthesis of a new series of diketopiperazine and spirooxoindolethiazolidine derivatives and the preliminary results of their biological activity.…”

Enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes catalyzed by binaphthyl-derived organocatalysts

“…Many of these naturally occurring naphthoquinones and their synthetic analogues are important precursors for the synthesis of natural products and pharmaceuticals [5–9]. The stereoselective formation of C–C bonds is of great importance for the synthesis of enantiomerically pure, biologically active organic compounds [10–11].…”

Synthesis of spiroheterocycles derived from benzo[f]chromanone

“…Proliferation of research in spiro chemistry has now attained considerable height, right from the unprecedented synthesis of spiro hydrocarbon by Bayer [1]. Spiro heterocycles in particular fused at a central carbon atom display diverse biological and pharmaceutical [2–7] activities due to their interesting conformational features and structural implications. The presence of the sterically constrained spiro structure in various natural products also generates interest in the investigation on spiro compound [8, 9].…”