1,5-Dimethyl-6H-pyridazino[4,5-b]carbazole, a 3-Aza Bioisoster of the Antitumor Alkaloid Olivacine.

Abstract

Olivacine (1,5-dimethyl-6H-pyrido[4,3-b]carbazole) is a member of the pyridocarbazole family of alkaloids. It was first isolated from the bark and stem of Aspidosperma olivaceum 2) and it has been found to possess similar antitumor activity as its 5,11-dimethyl isomer, ellipticine, and related compounds like 9-methoxyellipticine. 3,4) As the main mechanism of these agents' antineoplastic action, a stabilization of the "cleavable complex" which is formed between DNA and the enzyme, topoisomerase II,5) is generally accepted, although additional mechanisms have been discussed for some pyridocarbazoles, e.g. reactivation of the lost functionality of the p53 protein.6) Based on the naturally occurring lead compounds, numerous modifications of this system have been studied, 7) leading to the development of drugs like elliptinium, 8) datelliptium, 9) retelliptine, 10) or pazelliptine. 11)More recently, the highly potent olivacine analog, S16020-2, 12,13) has attracted considerable attention due to its apparent ability to circumvent P-glycoprotein-mediated multidrug resistance. 14)Among the structural variations which have been described so far, there are several examples for incorporation of an additional nitrogen atom into the tetracyclic skeleton, like in the case of 9-aza-ellipticine 15) or pazelliptine. 11,16) Based on previous investigations in the 3-aza-ellipticine series by Landelle et al.,17) we recently reported the synthesis of several pyridazino [4,5-b]carbazoles, some of which exhibited significant antitumor activity.18) In the course of our ongoing research in this field, we now became interested in the synthesis of the hitherto unknown title molecule, 1,5-dimethyl-6H-pyridazino [4,5-b]carbazole, as a 3-aza isoster of olivacine, which was required as a reference compound. Until now, only one method for the preparation of 1,5-dialkyl-6H-pyridazino[4,5-b]carbazoles has been described, which is based on a ring transformation of 5-acyl-11H-pyrido [4,3-a]carbazoles under Wolff-Kishner conditions. 19) However, this sequence inherently leads to 5-ethyl-substituted pyridazino [4,5-b]carbazoles and thus cannot be adopted to the synthesis of our target structure. Here, we wish to report on a short synthesis of 3-aza-olivacine and on the results of an initial in-vitro testing for antitumor activity.In a first approach to the 1,5-disubstituted pyridazino [4,5-b]carbazole skeleton, we investigated the selective addition of methyllithium to an appropriate 1-methylcarbazole-2,3-dicarboxylic acid derivative. After some unsuccessful attempts with the corresponding anhydride, we employed the protected N-phenylimide (5) as the electrophile. This compound can be easily prepared starting from commercially available 1-methylpyrano[3,4-b]indol-3(9H)-one 20) (1) by Diels-Alder reaction with dimethyl acetylenedicarboxylate which gives the diester (2), 20,21) followed by ester hydrolysis and subsequent formation of the cyclic anhydride (3). 22) Heating of the latter with excess aniline, followed by protection of the carbazole nitr...

The anticancer potential of various substituted pyridazines and related compounds

“…The compound represents a new 3-aza analogue of the antitumor natural product, olivacine. A pyrido [4, 3-b] carbazole-type alkaloids, the antitumor natural product, olivacine (Haider N, Sotelo. 2002), represents a new 3-aza analogue of the antitumor natural product, olivacine and their structural modifications will be carried out, aiming at an enhancement of antineoplastic activity (Norbert and Eddy 2002).…”

Synthesis of ortho-Functionalized 4-Aminomethylpyridazines as Substrate-Like Semicarbazide-Sensitive Amine Oxidase Inhibitors

“…It is well known that exchange of a pyridine by a diazine (and especially by a pyridazine) can significantly alter the physicochemical properties of a compound (lower basicity, higher dipole moment, increased water solubility), as demonstrated, for instance, with some aza analogues of the pyridocarbazole alkaloids. 8,9) Here, we wish to report on the synthesis and preliminary in-vitro biological evaluation of a series of new 4-aminomethylpyridazine derivatives ("diaza-benzylamines") with various alkylamino side chains located at one or both positions ortho to the CH 2 NH 2 moiety. Despite the close structural similarity between the envisaged 4-aminomethylpyridazines and the known 4-aminomethylpyridine lead compounds, we had to develop different synthetic strategies in order to make the target compounds accessible.…”

“…Vilsmeier-Haack formylation of these electronrich pyridazinones then afforded the aldehydes 7a, b. 17) Treatment of the crude aldehydes with hydroxylamine hydrochloride/sodium acetate in aqueous ethanol smoothly gave the corresponding oximes (8). These new compounds were obtained either as an E/Z mixture (in the case of 8a) or as the pure E-configured isomer (in the case of 8b), as determined by 1 H-NMR spectroscopy (nuclear Overhauser effect (NOE) between the aldehydic proton and the N-OH proton of the E-oxime; see Experimental).…”

2-[4-[Bis(2-chloroethyl)amino]benzyl]-5,5-dimethyl-2,5-dihydro-4H-benzo[e]isoindol-4-one (Cytotoxic Oxonaphthalene-Pyrroles, Part I)

“…The cytotoxic effects are based on the highly active aziridinium cation intermediates arising from the bis(2-chloroethyl)amine moiety [1]. In continuation of our department's previous studies in the field of antitumor agents [2][3][4][5][6][7][8] we are reporting in this paper the synthesis of the oxonaphthalene annelated pyrrole 3 with an attached side chain containing a bis(2-chloroethyl)amine group. The cytotoxic activity of 3 was evaluated.…”