A series of calothrixin B (2) analogues bearing substituents at the 'E' ring and their corresponding deoxygenated quinocarbazoles lacking quinone unit were synthesized. The cytotoxicities of calothrixins 1, 2, and 15b-p and quinocarbazole analogues were investigated against nine cancer cell lines. The quinocarbazoles 21a and 25a inhibited the catalytic activity of human topoisomerase II. The plasmid DNA cleavage abilities of calothrixins 1, 2, and 15b-p identified compound 15h causing DNA cleavage comparable to that of calothrixin A (1). Calothrixin A (1), 3-fluorocalothrixin 15h and 4-fluoroquinocarbazole 21b induced extensive DNA damage followed by apoptotic cell death. Spectral and plasmid unwinding studies demonstrated an intercalative mode of binding for quinocarbazoles. We identified two promising drug candidates, the 3-fluorocalothrixin B 15h with low toxicity in animal model and its deoxygenated derivative 4-fluoroquinocarbazole 21b as having potent cytotoxicity against NCI-H460 cell line with a GI of 1 nM.
An efficient nickel-catalyzed
acceptorless dehydrogenative coupling
of methyl-substituted heteroarenes with primary alcohols is achieved
using an in situ generated complex of inexpensive NiBr2 and readily available 8-aminoquinoline picolinic amide ligand. The protocol is operationally simple
and scalable and furnishes a series of high-value 2-alkenylheteroarenes
in good yields (up to 88%) with exclusive E-selectivity.
The reaction proceeds with the release of water and molecular hydrogen,
which was analyzed through gas chromatography to validate the reaction
mechanism.
A novel one pot synthesis of calothrixin B and its analogs is achieved involving an FeCl3-mediated domino reaction of enamines in dry DMF at reflux. Alternatively, the enamines upon interaction with CuBr2 in DMF at reflux led to the formation of 1-phenylsulfony-2-(2'-nitroaryl)-4-hydroxycarbazole-3-carbaldehydes in excellent yields.
The total synthesis of calothrixin B and its analogs was achieved starting from 2‐methylindole. The synthesis involved an electrocyclization of 2‐nitroarylvinyl‐3‐phenylsulfonylvinylindoles as a key step to give 2‐nitroaryl‐4‐methoxy‐3‐methylcarbazoles. Oxidation of these compounds followed by reductive cyclization led to N‐phenylsulfonylquinocarbazoles. These quinocarbazoles underwent hydrolysis and aerial oxidation in one pot to give the target compounds.
Key indicators: single-crystal X-ray study; T = 296 K; mean (C-C) = 0.005 Å; R factor = 0.053; wR factor = 0.172; data-to-parameter ratio = 12.3.In the title compound, C 25 H 15 ClN 2 O 6 S, the carbazole ring system is essentially planar, with a maximum deviation of 0.152 (3) Å for the C atom to which the 4-chloro-2-nitrophenyl ring is attached. Its mean plane is almost orthogonal to the phenylsulfonyl and nitrophenyl rings, making dihedral angles of 82.64 (14) and 79.89 (13) , respectively. The N atom of the nitro group deviates by 0.032 (3) Å from the benzene ring to which it is attached. The molecular structure features intramolecular O-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds, which generate three S(6) ring motifs. In the crystal, molecules are linked by C-HÁ Á ÁO hydrogen bonds, which generate C(6) and C(9) chains running in the [100] and [010] directions, respectively, forming a two-dimensional network lying parallel to (001). There are also R 4 3 (28) supramolecular graph-set ring motifs enclosed within these networks.
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