title: Antitumoral activity of a new series of 5,6-dihydrobenzo(a)carbazoles.
abstract: The overlapping of three-dimensional structures of 5,6-dihydrobenzo(a)carbazole (DHBC) derivatives over the structure of 4-hydroxytamoxifen (4-OH-TAM), by means of the MDL CHEMLAB 11.0 computational program, shows a reasonable structural and spatial resemblance. This finding raised the hypothesis of their possible antitumoral activity, similar to that of tamoxifen (TAM). A number of DHBCs with an alkyl chain and a second basic nitrogen as substituent were synthesized in our laboratory and their possible antitumoral activity was tested by means of: 1) competitive radioligand assays to determine relative drug affinity for the estrogen receptor (ER); 2) in vivo studies, giving the synthetic drugs subcutaneously (1 mg kg-1 day-1) to Sprague-Dawley rats with N-nitroso-N-methylurea (NMU)-induced mammary tumors; and 3) in vitro cell proliferation experiments employing the soft agar clonogenic technique. Besides, studies on toxicity and histopathological analyses of organs and tumors from treated animals were performed. Results obtained showed that: 1) relative binding affinities (RBA) for the ER were similar to that of TAM; 2) some structures showed significant antitumoral activity and induced tumoral regression similar to TAM; and 3) these compounds had in vitro inhibitory effect on cell proliferation. Even though all the compounds of the series of synthesized DHBCs showed affinity for the ER similar to TAM, the results of in vivo experiments confirmed the crucial role of hydroxyl groups in the molecule and of the interatomic distance between them, similar to that of estradiol, as well as the necessary presence of the aminoalkyl chain on the annular N atom. However, the effect of alkyl chain enlargement in the nitrogen substituent on the biological activity of those drugs is as yet unclear.
authors.affiliation: Laboratorio de Radioisótopos, Cátedra de Física, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Martin
authors.forename: Claudia
authors.initials: C
authors.lastname: Cocca
authors.forename: Elena
authors.initials: E
authors.lastname: Rivera
authors.forename: Graciela
authors.initials: G
authors.lastname: Cricco
authors.forename: Ricardo
authors.initials: R
authors.lastname: Caro
authors.forename: Adriana
authors.initials: A
authors.lastname: Segall
authors.forename: Horacio
authors.initials: H
authors.lastname: Pappa
authors.forename: Raul
authors.initials: R
authors.lastname: Casaubon
authors.forename: María T
authors.initials: MT
authors.lastname: Pizzorno
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Bergoc
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D004958:Estradiol / Q000378:metabolism; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D008770:Methylnitrosourea; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D013629:Tamoxifen; D004958:Estradiol; D008770:Methylnitrosourea