Synthesis of Pyridazino[4,5-b]carbazoles as Potential Antitumor Agents

Haider, N.; Jbara, Rami; Khadami, F.; Wanko, Richard

doi:10.3987/com-98-8217

Cited by 32 publications

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“…For all cell lines, growth inhibitory activity of 14 was found to exceed that of the 5-monomethyl congener (15), the synthesis of which we had reported recently. 18) In conclusion, a series of b-fused carbazoles could be made available, utilizing the Diels-Alder reaction of 1-methylpyrano [3,4-b]indol-3(9H)-one (1) with electron-deficient acetylenic dienophiles as the key step. Employment of a 4-oxo-2-pentynoic acid ester in this cycloaddition reaction thus permits the synthesis of the title compound (14) as a new 3-aza bioisoster of the natural product, olivacine, in only four steps from commercially available material.…”

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confidence: 99%

“…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.…”

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confidence: 99%

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

Haider

Sotelo

2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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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...

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

Haider

Sotelo

2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Among the structural variations, incorporation of an additional nitrogen atom into the tetracyclic skeleton, like in the case of 9-aza-ellipticine or pazelliptine. Based on previous investigations in the 3-aza-ellipticine series, several pyridazino [4, 5-b] carbazoles, some of which exhibited significant antitumor activity (Haider, et al, 1998;Spreitzer, et al, 2007;Haider, and Käferböck. 2004).…”

Section: Anticancer Activity Of Natural Pyridazines Agentsmentioning

confidence: 99%

The anticancer potential of various substituted pyridazines and related compounds

Asif¹

2014

IJAC

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Pyridazine nucleus exhibited immense pharmacological activities. Pyridazine nucleus is present in various compounds that possess remarkable pharmacological activities. Various pyridazinone compounds have antitumor activity. Some of them pyridazinone derivatives bearing different moieties were exhibited excellent anticancer activity toward human cancer cell lines. They showed remarkable activity against leukemia, non-small cell lung cancer, colon, central nervous system, melanoma, ovarian and breast cancer cell lines. These compounds were act by different mechanism. Keywords: Pyruvate Kinase; Anti-Cancer; Pyridazines; Biological Activities; Cytotoxicity.

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“…The latter compounds 11 had been designed as tricyclic analogs of tetracyclic anticancer agents of the ellipticine type, and they had been found to exhibit significant cytotoxic activity despite "shrinking" the pyrido [4,3-b]carbazole into a pyrido [4,3-b]indole scaffold. As we had previously demonstrated that also pyridazino [4,5-b]carbazoles (3-azaellipticines) bearing appropriate substituents show comparable activity in antitumor assays, 12 we became interested in the synthesis of 4-methylpyridazino [4,5- …”

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confidence: 99%

Synthesis of 3-azaharman and other new azacarbolines of the pyridazino[4,5-b]indole type

El‐Kashef¹,

Farghaly²,

Floriani³

et al. 2004

Arkivoc

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Synthesis of Pyridazino[4,5-b]carbazoles as Potential Antitumor Agents

Cited by 32 publications

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

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

The anticancer potential of various substituted pyridazines and related compounds

Synthesis of 3-azaharman and other new azacarbolines of the pyridazino[4,5-b]indole type

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