Anti-Cancer Agents in Medicinal Chemistry, 2012, 12, 611-618.

Anticancer activity and anti-inflammatory studies of 5-Aryl-1,4-benzodiazepine derivatives

Cortez-Maya Sandraa*, Cortés Cortés Eduardoa, Hernández-Ortega Simóna, Ramírez Apan Teresaa, Nieto Camacho Antonioa, Irina V. Lijanovab and Martínez-García Marcosa

aInstituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Circuito Exterior, Coyoacán, C.P. 04510México D.F., México; bInstituto Politécnico Nacional, CIITEC, Cerrada Cecati S/N, Colonia Santa Catarina de Azcapotzalco, C.P. 02250, México D.F., México.



Benzodiazepines represent a large and still expanding group of synthetic heterocyclic derivatives. The wide spectrum of the pharmacological effects exhibited by these compounds makes them one of the most versatile classes of drugs used in psychopharmacology. They are widely used as anticonvulsant, antianxiety, analgesic, sedative, anti-depressive, hypnotic and anti-inflammatory agents. During last few decades large number of reports has appeared of literature highlighting the anticancer activity of [1,4-benzodiazepines]. Here in this work, we discussed the synthesis of 5-aryl-1,4-benzodiazepines with chloro- or fluoro-substituents in the C ring,  and their anti-inflammatory, myeloperoxidase and anticancer properties. The synthesized compounds showed good anti-inflammatory and anticancer activities, which were enhanced in the presence of a chloro-substituent in the C ring of the 5-aryl-1,4 benzodiazepine.

KEYWORDS: Anticancer activity, anti-inflammatory, 1,4-benzodiazepines, myeloperoxidase.



Benzodiazepines have attracted much attention in the field of drugs and pharmaceuticals in the last 30 years. The wide spectrum of the pharmacological effects exhibited by these compounds makes them one of the most versatile classes of drugs used in psychopharmacology and recently  have been evaluated for their ability to inhibit the proliferation of tumor cells, and this effect has been correlated with PBR binding characteristics. The biological relevance of the benzodiazepine family explains our interest in the synthesis of derivatives 1,4-benzodiazepines. We describe the synthesis of 5-aryl-1,4-benzodiazepines with a chloro or nitro group in the ring A and chloro or fluoro group in the ortho position in the ring C, these were synthesized in three steps from the 2-amino-4-chloro or 2-amino-4-nitrobenzophenones. All compounds were characterized by spectroscopy techniques and their structure was confirmed by X-ray diffraction analysis of a single crystal.Sandra Cortez-Maya fig1

From the series of synthesized 5-aryl-1,4-benzodiazepines (1316), were evaluated their biological activity against cancer and were screened in vitro against five human cancer cell lines. PC-3 (human prostate cancer), K-562 (human chronic myelogenous leukemia), and HCT-15 (human colorectal adenocarcinoma), MCF-7 (human breast cancer) and SKLU-1 (human lung adenocarcinoma) cell lines were supplied by National Cancer Institute (USA). The human tumor cytotoxicity was determined using the protein-binding dye sulforhodamine B (SRB) in microculture assay to measure cell growth, the initially obtained cytotoxic screening data show that they have activities, especially halogen-substituted ones, and that the activity depends on the nature of the human cancer cell line. Generally, the in vitro experiments revealed a good activity of tested compounds in particular, PC-3 human prostate cancer cells appeared to be more sensitive to the growth inhibition by tested compounds than SKLU cancer cells. The most interesting result was related to compound 14, which was found to be the best inhibitor of this series against both PC-3 and HCT-15 cell lines with IC 50 of 1.5±0.7 and 5.2±0.90, respectively. In addition all tested compounds showed anti-inflammatory activity, and we observed that only compounds possessing significant anti-inflammatory properties demonstrated anticancer properties. Among them, compounds 14 and 15 emerged as the most promising PC-3, HCT-15 and SKLU-1 inhibitors. In summary, these results revealed a correlation between cell growth inhibitory and anti-inflammatory activities of 5-aryl-1,4-benzodiazepines with o-chloro in the ring C, and further investigation is warranted to establish the mechanism of inhibitory activity.

ACKNOWLEDGEMENTS: This study was supported by DGAPA-UNAM (IN202010-3 and DGAPA IN211112) grant. We would like to thanks Peña Gonzalez M. A. and Huerta Salazar E. for technical assistance.

CONTACT:Sandra Cortez-Maya fig2

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