ChemInform Abstract: STRUCTURE‐ACTIVITY RELATIONSHIPS IN A SERIES OF NEWLY SYNTHESIZED 1‐AMINO‐SUBSTITUTED ELLIPTICINE DERIVATIVES

Ducrocq, Claire; Wendling, Françoise; Tourbez-Perrin, M.; Rivalle, C.; Tambourin, P; Pochon, F; Bisagni, Émile; Chermann, Jean‐Claude

doi:10.1002/chin.198113269

Cited by 2 publications

(1 citation statement)

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“…It should be noted that this general strategy of cryptolepines allowed the preparation of an analogue of ellipticine 45 (a natural alkaloid with antitumor activities 34 ) and the first total synthesis of 11-isopropylcryptolepine 13 (2d), isolated in 1999 from the root of C. sanguinolenta.…”

Section: Chemistrymentioning

confidence: 99%

New Synthesis of Benzo-δ-carbolines, Cryptolepines, and Their Salts: In Vitro Cytotoxic, Antiplasmodial, and Antitrypanosomal Activities of δ-Carbolines, Benzo-δ-carbolines, and Cryptolepines

et al. 2001

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The paper describes, in its first part, a new synthesis of benzo-delta-carbolines, cryptolepines, and their salts. The strategy is based on the association between halogen-dance and hetero-ring cross-coupling. It is fully convergent and regioselective with interesting overall yields from 27% to 70%. A halogen-dance mechanism in quinoline series is also proposed. The formal synthesis of potential antimalarial compounds and the first total synthesis of 11-isopropylcryptolepine are also described. In the second part, cytotoxic activity against mammalian cells and activities against Plasmodium falciparum and Trypanosoma cruzi of benzo-delta-carbolines and delta-carbolines were evaluated in vitro to study the structure-activity relationships. For benzo-delta-carbolines, methylation at N-5 increases the cytotoxic and antiparasitic activities. A further alkylation on C-11 generally increases the cytotoxic activity but not the antiparasitic activity, cryptolepine and 11-methylcryptolepine being the most active on both parasites. Taking advantage of the fluorescence of the indoloquinoline chromophore, cryptolepine was localized by fluorescence microscopy in parasite DNA-containing structures suggesting that these compounds act through interaction with parasite DNA as proposed for cryptolepine on melanoma cells. For delta-carbolines, methylation at N-1 is essential for the antimalarial activity. 1-Methyl-delta-carboline specifically accumulates in the intracellular parasite. It has weak cytotoxic activity and can be considered as a potential antimalarial compound.

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Section: Chemistrymentioning

confidence: 99%

New Synthesis of Benzo-δ-carbolines, Cryptolepines, and Their Salts: In Vitro Cytotoxic, Antiplasmodial, and Antitrypanosomal Activities of δ-Carbolines, Benzo-δ-carbolines, and Cryptolepines

et al. 2001

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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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ChemInform Abstract: STRUCTURE‐ACTIVITY RELATIONSHIPS IN A SERIES OF NEWLY SYNTHESIZED 1‐AMINO‐SUBSTITUTED ELLIPTICINE DERIVATIVES

Abstract: Die Chlorellipticine (I) werden mit Aminen in die Verbindungen (II) übergeführt.

Cited by 2 publications

References 1 publication

New Synthesis of Benzo-δ-carbolines, Cryptolepines, and Their Salts: In Vitro Cytotoxic, Antiplasmodial, and Antitrypanosomal Activities of δ-Carbolines, Benzo-δ-carbolines, and Cryptolepines

New Synthesis of Benzo-δ-carbolines, Cryptolepines, and Their Salts: In Vitro Cytotoxic, Antiplasmodial, and Antitrypanosomal Activities of δ-Carbolines, Benzo-δ-carbolines, and Cryptolepines

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

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