Weight loss effects of quaternary salts of 5-amino-1-(chloromethyl)-1,2-dihydro-3H-benz[e]indoles; structure–activity relationships

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 2; pp. 734 - 749
• Main Authors: Tercel, Moana, Stevenson, Ralph J., Lu, Guo-Liang, Stribbling, Stephen M., Wilson, William R., Tatnell, Michele A., Marnane, Rebecca N., Mountjoy, Kathleen G., Denny, William A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-01-2012
• Subjects: absorption; adenine; adipose tissue; AminoCBI; Animals; anorexia; Benz[e]indole; bile; cell death; Cyclopropanes - chemistry; DNA; hydrogen; indoles; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Male; Mice; Mice, Inbred C3H; Quaternary salt; salts; Salts - chemistry; SAR study; spleen; Structure-Activity Relationship; structure-activity relationships; triacylglycerols; weight control; weight gain; Weight loss; Weight Loss - drug effects; DIPEA; ip; Weight loss; Quaternary salt; AIBN; CBI; SAR study; AminoCBI; CSA; NMP; Benz[e]indole; DMAP; pyBOP; DMA; EDCI·HCl
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.12.007

Quaternary salt analogues based on the DNA minor groove binder and adenine N3 alkylating agent 5-amino-1-(chloromethyl)-1,2-dihydro-3H-benz[e]indole (aminoCBI) show remarkable effects on the body weight of mice (a long-term failure to gain weight relative to matched controls with no loss of appetite or perceptible deterioration in health) following administration of a single (non-toxic) dose between about 0.5–5μmol/kg. The nature of the quaternizing group was not important, but a related hydroxyCBI analogue was much less effective. Compounds where the chloro group was replaced by a hydrogen or hydroxy group (thus abrogating DNA alkylating capability) showed no weight control activity. It is speculated, based on other studies, that the marked long-term weight control effect is due to inhibition of bile flow into the intestine and reduced absorption of triglycerides, together with accelerated cell death in spleen and white adipose tissues due to drug accumulation there. This class of compound may serve as interesting tools for further study of these phenomena.