Synthesis and Evaluation of 9-Hydroxy-5-methyl- (and 5,6-dimethyl)-6H-pyrido[4,3-b]carbazole-1-N-[(dialkylamino)alkyl]carboxamides, a New Promising Series of Antitumor Olivacine Derivatives

Abstract

Starting from 2-(2-aminoethyl)-6-methoxy-1-methylcarbazole, ethyl 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-carboxylate was obtained through a three-step sequence. This compound and its 6-methyl derivative react with (dialkylamino)alkylamines to provide various 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-(N-substituted carboxamides) whose boron tribromide demethylation afforded corresponding 9-hydroxy-1-(N-substituted carbamoyl)-olivacines. The same pathway but starting from 2-(2-aminoethyl)-6-methoxy-1,4-dimethylcarbazole led to ethyl 9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxylate which did not normally react with amines. It provided either the recovered starting material at 120 degrees C or 9-methoxyellipticine resulting from an unexpected decarboethylation in a steel vessel at 180 degrees C. Biological testing of the newly obtained 1-carbamoylolivacine derivatives showed that 9-hydroxylated compounds displayed high cytotoxicity for cultured L1210 and colon 38 cells (IC50 range 5-10 nM) and good antitumor activity in vivo in the P388 leukemia and colon 38 models when administered by the iv route. The most active compound in these series is 9-hydroxy-5,6-dimethyl-1-[N-[2-(dimethylamino)ethyl]carbamoyl]-6H- pyrido[4,3-b]carbazole which was selected for further evaluation on murine solid tumors and for toxicological studies.

DNA Binding Ellipticine Analogues: Synthesis, Biological Evaluation, and Structure–Activity Relationships

“…The most active of these derivatives, S16020-2 (NSC-659687) (Figure 1), has shown a broad range of antitumor activities against a panel of murine and human tumor xenografts. [22][23][24] It has also been suggested that DNA topo II is the intracellular target of S16020-2, and that the interaction of S16020-2 with this enzyme is strongly influenced by the N-[2(dimethylamino)ethyl]carbamoyl side chain.…”

Synthesis and Anticancer Activity of New 1‐Substituted‐6H‐pyrido[4,3‐b]carbazole Derivatives

“…All of the newly obtained compounds were analyzed for C, H, and N and the analytical results were within l 0.4% of the theoretical values. The starting compound 2-(6-methoxy-1-methyl-9H-carbazol-2-yl)ethylamine 4 (Scheme 1) was prepared according to the described procedure [13].…”

“…One of the olivacine derivatives namely 9-hydroxy-5,6-dimethyl-N-[2-(dimethylamino)ethyl]-6H-pyrido [4,3-b]carbazole-1-carboxamide (S 16020) is actually in the course of clinical trials [13,14]. S 16020 demonstrated a broad spectrum of antitumor activity on murine P388 leukemia, Lewis lung carcinoma, B16 melanoma, M5076 sarcoma and human colon, breast, ovary, lung tumor models [15 -17].…”

Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: Exploring the scope of indole and carbazole derivatives

“…During the synthesis and evaluation of olivacine derivatives, [38] the cytotoxic compound S16020 (aka NSC 659687) was found (Figure 8), [39] which was later discovered to be a potent and selective topoisomerase II inhibitor. S16020 has since completed a Phase I clinical study, [41] and more recently has been tested on xenografts of medulloblastoma and glioblastoma, [42] where it unfortunately showed lower activity than the positive control, doxorubicin.…”