Biological Evaluation of Dipyrromethanes in Cancer Cell Lines: Antiproliferative and Pro‐apoptotic Properties

Abstract

Functionalized dipyrromethanes were synthesized by hetero-Diels-Alder reactions of nitroso- and azoalkenes and screened for their in vitro activity as anticancer agents. The studied dipyrromethanes were tested against leukemia and lymphoma cell lines, and showed GI values in the mid-micromolar range. The pro-apoptotic activities of two candidates, (E)-1-(2'-ethoxycarbonylhydrazono-1'-benzyl-1H-tetrazol-5-yl)-5,5'-diethyldipyrromethane and (E)-1-(2'-p-nitrophenyl-2'-hydroxyiminoethyl)-5-phenyldipyrromethane, and their effects on the cell cycle are described. The latter compound was found to decrease the S-phase cell population in a dose-dependent manner and to irreversibly block cells in the G /M phase.

Asymmetric Neber Reaction in the Synthesis of Chiral 2-(Tetrazol-5-yl)-2H-Azirines

“…14 On the other hand, we reported the synthesis of (1H-tetrazol-5yl)-allenes, 15 tetrazolyl-tryptamines and 2-halo-2-(tetrazol-5yl)-2H-azirines and the use of these compounds for the construction of tetrazolyl-heterocycles, namely 3-tetrazolyl-βcarbolines with anti-cancer activity. [15][16][17][18] Building blocks bearing a tetrazolyl substituent are a particularly interesting synthetic tool to explore carboxylic acid/tetrazole bioisosterism as a way to find new molecules with enhanced biological activity. In this context, we have selected 2-(tetrazol-5yl)-2H-azirines as our target molecules due not only to their interesting chemical features but also considering that these heterocycles are bioisosters of relevant 2H-azirine-2carboxylates.…”

“…The observed molecular conformation in the crystal maximizes the ππ interaction between the electron clouds of the phenyl rings and effects. As the molecules lacks any strong H-bonding donor, the only significant intermolecular interactions spotted in the crystal structure involve C-H groups acting as donors (D) and N or O atoms as acceptors (A), namely C(15)-H(15)...N(5) i , i = 1-x,1-y,1-z (D…A = 3.435(4) Å) and C(22)-H(22) ...O(17) ii , ii = 2-x,-1/2+y,3/2-z (D…A=3.466(3) Å). In addition, the two short intramolecular contacts C(9)-H(9A)...N(1) (D…A = 3.102(3) Å) and C(15)-H(15) ...N(8) (2.861(3) Å) deserve to be remarked.…”

Meso-Substituted Corroles from Nitrosoalkenes and Dipyrromethanes

“…In both cases, the products were isolated as a mixture of E and Z isomeric oximes. Based on 1 H NMR data of other isomeric oximes, , including 1-(2′-hydroxyiminoethyl)-dipyrromethanes and meso -(hydroxyiminomethyl)-dipyrromethanes, , the configuration of the oxime group could be assigned. In the 1 H NMR spectrum, the meso -proton of bilane bearing a Z -oxime appears at a lower chemical shift than the value observed for the derivative with the E -oxime.…”

“…It has been previously observed that the chemical behavior of nitrosoalkenes toward pyrroles and dipyrromethanes is strongly dependent on the nature of the 3- and/or 4-substituents. ,,, In fact, conjugated nitrosoalkenes bearing a tetrazolyl, ester, or phosphinyl group react with pyrroles via hetero-Diels–Alder reaction, whereas 1-arylnitrosoethylenes react through conjugate addition affording two isomeric oximes. Interestingly, an easy and unambiguous way to determine the mechanism pathway is the outcome of the reaction regarding the selectivity of oxime formation, single stereoisomer versus E / Z mixtures.…”

Current Advances in the Synthesis of Valuable Dipyrromethane Scaffolds: Classic and New Methods

“…Dipyrromethanes synthesized by this approach have the unique feature of being meso -substituted with oxime and hydrazone moieties [86]. The same research group described the functionalization of dipyrromethanes at positions 1 and/or 9 through hetero-Diels-Alder reaction or conjugated addition of nitrosoalkenes and azoalkenes [88,89,90].…”