Synthesis and Biological Evaluation of Indoloquinolines and Pyridocarbazoles: A New Example of Unexpected Photoreduction Accompanying Photocyclization

Abstract

Interest in the chemistry of pyridocarbazoles and indoloquinolines has increased this last decade since these skeletons are present in a large number of alkaloids of biological interest. For example, the indoloquinoline type alkaloid cryptolepine 1 (Fig. 1) extracted from the roots of Cryptolepis sanguinolenta 1) has been shown to exhibit antiplasmodial, 2) antibacterial 3) and cytotoxic properties. 4,5) This last activity is due to cryptolepine intercalation into DNA and subsequent inhibition of DNA religation by topoisomerase II. 5) Another example concerns the pyridocarbazole type alkaloid ellipticine 2 (Fig. 1) extracted from the leaves of Ochrosia elliptica 6) which has exhibited cytotoxic properties by different mechanisms : intercalation into DNA, 7) inhibition of topoisomerase II,8) formation of covalent adducts with DNA after bioactivation, 9) stimulation of apoptosis. 10) Different linear and angular analogs of these compounds have already been synthetized by several groups [11][12][13][14][15][16][17] but the series of indolo [2,3-c]quinoline and pyrido [2,3-c]carbazole haven't been studied yet.Therefore, as a part of our program concerning the elaboration of analogs of natural products, we are interested in the chemistry as well as in the biological activities of these angular heterocycles. 18,19) Our methodology resides in the photocyclization of enaminones derived from 3 or 6-aminoquinoline ( Fig. 1). Enaminones represent convenient tools in heterocyclic chemistry since they can be implicated in the elaboration of carbazoles, 20) a-carbolines, 21) b-carbolines and dcarbolines.22,23) The photocyclization can occur through an electrocyclization for tertiary enaminones or through a radical process for halogenated enaminones.24) Furthermore, in our recent works, we obtained N-benzylpyridocarbazoles and indoloquinolines from tertiary N-benzylenaminones 25) and non N-substituted compounds from secondary iodinated enaminones. 26) In the present work, we investigate the reactivity of tertiary enaminones carrying an alkyl or a dialkylaminoalkyl side chain 3 and report the results of in vitro cytotoxicity studies of the obtained cyclized compounds 4. ChemistryFirtsly, the reactivity of tertiary enaminones derived from 3-aminoquinoline was studied. According to previously described procedures, 22,23,25,26) the secondary enaminone 7 is obtained by condensation of 3-aminoquinoline 5 and 1,3-cyclohexandione 6 in toluene with catalytic amounts of p-toluenesulfonic acid. Then, a methyl or a diethylaminoethyl side chain was introduced on the enaminone nitrogen by treating secondary enaminone 7 by sodium hydride, and then by methyl iodide or by the hydrochloride salt of diethylaminoethylchloride to give 8 and 9. The dimethylaminopropyl side chain couldn't be introduced following this protocole. However, the tertiary enaminone 10 was obtained by treating compound 7 with the hydrochloride salt of dimethylaminopropylchloride in presence of sodium hydride in dimethylformamide (DMF) 27) (Fig. 2). The methyl substituent w...

Structure−Activity Relationships of Highly Cytotoxic Copper(II) Complexes with Modified Indolo[3,2-c]quinoline Ligands

“…The pharmacological relevance of indoloquinolines is also demonstrated by the fact that isocryptolepine, a derivative of indolo[3,2- c ]quinoline, and the closely related cryptolepine, a derivative of indolo[3,2- b ]quinoline, could be isolated from the roots of Cryptolepis sanguinolenta , an African plant used in traditional medicine to fight malaria. − Whereas cryptolepine was extensively studied for its medicinal applicability, isocryptolepine and further indolo[3,2- c ]quinolines were only explored by researchers to a limited extent, although their antiproliferative activity in vitro has been confirmed. − …”

Formation of 3-Aminophenols from Cyclohexane-1,3-diones

“…When cyclohexanedione was condensed with a primary amine the next step required N -alkylation, and this was achieved by deprotonation with NaH in DMF followed by addition of an alkyl or benzyl halide (MeI, BnCl) …”

“…achieved by deprotonation with NaH in DMF followed by addition of an alkyl or benzyl halide (MeI, BnCl). 15 The 3-aminocyclohex-2-en-1-ones we have studied are listed in Table 1. In the two cases where the same product was made by direct use of a secondary amine and also by the two-step method involving a primary amine followed by N-alkylation, the single step process gave a higher yield.…”

Novel Synthetic Investigation in the Field of Indolo[2,3-B]quinoxaline Ring Containing Tetracyclic and Pentacyclic Heterocycles

“…They combine on the one hand, a cycle of electron-rich indole core, on the second hand, a fragment of electro-deficient quinoxaline that creates great interest among researchers. Discussion of indole-quinoxaline derivatives is an object of interest in terms of its pharmacological activity, which is basically conditioned by the capacity of intercalation with DNA (Gu et al, 2017;Peczynska-Czoch et al, 1994;Aragon et al, 2007). They are known to have anti-virus, anti-fungal and cytotoxic activities (Moorthy et al, 2010;Wilhelmsson et al, 2008).…”