Synthesis and Cytotoxic Activity of Pyranocarbazole Analogues of Ellipticine and Acronycine

Abstract

Natural products including a carbazole basic skeleton fused with another heterocyclic system currently receive a strong attention, due to the promising antitumor properties of several of their representatives.1) Of particular interest in this field are the pyrido [4,3-b]carbazole alkaloids and the indolo[2,3-a]carbazole antibiotics. The first series, illustrated by ellipticine (1) and 9-methoxyellipticine (2), both isolated from Ochrosia species (Apocynaceae) include compounds which act by intercalation within the DNA-double strand, followed by inhibition of topoisomerase II.2) A derivative of ellipticine, elliptinium (3), has been commercialized for the treatment of metastatic breast cancer.3) Rebeccamycine (4), isolated from Saccharothrix aerocolonigenes, is a typical representative of the second series currently under clinical trials. It induces topoisomerase I mediated DNA-cleavage. 4)The antitumor activity of several related indolocarbazoles has been recently discussed. 5)The structurally related pyrano[2,3-c]acridone alkaloid acronycine (5) isolated from Achronycia baueri SCHOTT. (Rutaceae) was shown to exhibit antitumor properties against a broad spectrum of solid tumor models.6-8) Nevertheless, its moderate potency and low water solubility rapidly appeared as severe drawbacks for a possible introduction into the clinic. A hypothesis of bioactivation of the 1,2-double bond of the chromene ring system of acronycine into the corresponding epoxide 9) led to the development of several series of more active structural analogues. The most significant improvements were obtained with diesters of 1,2-dihydroxy-1,2-dihydroacronycine 10) and, more recently, of 1,2-dihy-11) Representatives of this latter series, such as diacetate 6, are considered as valuable candidates for clinical studies.12) The mechanism of their action implies alkylation of the 2-amino group of DNA guanine residues by the ester leaving group at position 1 of the drug. 13,14) We describe here the synthesis and cytotoxic properties of various 2,2,5,11-tetramethyl-and 2,2,5,6,11-pentamethyl-2,6-dihydropyrano[3,2-b]carbazole derivatives. Such compounds associate the 1,4-dimethylcarbazole tricyclic system responsible for the intercalating properties of ellipticine related drugs, with the dimethylpyran pharmacophore of acronycine derivatives. ChemistryFor the synthesis of 2,2,5,11-tetramethyl-2,6-dihydropyrano[3,2-b]carbazole (7), the readily available 1,4-dimethyl-9H-carbazole-3-carbaldehyde (8), previously used as key-intermediate in several ellipticine syntheses, 15) was chosen as starting material. It was first oxidized by use hydrogen peroxide in acidic medium, into the corresponding 1,4-dimethyl-9H-carbazol-3-ol (9), according to the Matsumoto's procedure which has been applied by Langendoen et al. to the synthesis of related hydroxycarbazoles.16) Construction of the fused dimethylpyran ring was ensured by condensation of 9 Various 2,2,5,11-tetramethyl-and 2,2,5,6,11-pentamethyl-2,6-dihydropyrano[3,2-b]carbazole derivatives were synthesized by c...

Facile Synthesis of Substituted Furo- and Pyrano-Carbazoles

“…for C 15 H 9 NO 3 : C,71.71;H,3.58;N,5.58%. Found: C,71.66;H,3.62;N,5.61%. [1,4]Oxazino [2,3,4-j,k]carbazole-1,2-dione (5d).…”

“…for C 14 H 7 NO 3 : C,70.88;H,2.95;N,5.90%. Found: C,70.94;H,2.98;N,5,6,2,phenanthridin-8-ones (6) and 3,4,5,carbazol-2(13H)-ones (7) General procedure. An appropriate mixture of the respective 1-hydroxycarbazoles (1, 1 mmol) and ethyl 2-oxocyclohexan-2-carboxylate (1 mmol) is treated 2974 K. PRABAKARAN AND K. J. R. PRASAD with fused ZnCl 2 =POCl 3 (1.5 g=6 mL) at 80 C for 6 h. The reaction was monitored by TLC.…”

“…[1][2][3][4][5] Naturally occurring 1-oxygenated carbazoles have attracted great interest because of their diverse and significant biological activity. [6] These alkaloids are mainly extracted from species of the genera Murraya and Clausena, and in the case of 2-and 3-substituted families, their biogenesis has been established.…”

Pattern recognition methods investigation of ellipticines structure–activity relationships

“…Ellipticine derivatives represent useful samples for such a purpose because lots of synthetic compounds of this group have been prepared and their structure-activity relationships have been screened [13][14][15][16]. In the last 10 years a great number of new synthetic routes have been proposed to ellipticines which encourage further investigation of active derivatives [15][16][17][18][19][20]. The main reasons for interest in ellipticines for clinical purposes are their limited toxic side effects and their complete lack of hematological toxicity [21].…”

Identification of Lead Compounds as Inhibitors of STAT3: Design, Synthesis and Bioactivity

“…It is noteworthy that carbazole derivatives show different biological profiles, such as:i nhibitiono fp roinflammatory cytokine biosynthesis;a ntiproliferative effect on SVR (murine endothelial cells) cells; [31] cytotoxic activity against human solid cancerc ells (PC3, DU145,a nd PA-1), [32] murine leukemia L1210 cell line, [33] human leukemic topoisomerase II sensitive (HL60N) and resistant (HL60 MX2) cell lines, [34] SK-N-SH humann euroblastoma (NB) cells. [35] Due to these multi-biological activities, the carbazole scaffold is considered ap rivilegeds tructure, [29] thus, able to bind different classes of macromoleculesw ith higha ffinity depending on the appropriate pattern of chemical substitutions.…”