title: Inhibitors of apoptosis in lymphocytes: synthesis and biological evaluation of compounds related to pifithrin-alpha.
abstract: The chemoprotection of cells from apoptosis induced by toxins or ionizing radiation could be important for biodefense and in the treatment of acute injuries. We describe a series of small heterocycles, including fused benzothiazoles, benzimidazoles, and related compounds, that abrogate thymocyte apoptosis induced by dexamethasone and gamma-irradiation. To optimize the protective activity of the previously reported pifithrin-alpha (PFT-alpha, 1), various derivatives and analogues of this and the corresponding ring-closed imidazobenzothiazole (IBT, 39) were synthesized. The aromatic analogues of 39 were more protective than 39, while the aromatic analogues of 1 were not active. Compound 19 containing a pyrrolidinyl substituent on the phenyl ring provided potent antiapoptotic activity (EC50 of 1.31 microM compared to 4.16 microM for 1). Modification of aromatic 39 with a pyrrolidinyl para substituent (compound 60) enhanced the activity, lowering the EC50 to 0.35 microM. Also, 60 provided significant protection against gamma-irradiation-induced apoptosis, as expected. Compounds 19 and 60 may be promising for potential clinical development.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0663, USA.
authors.forename: Sylvie D
authors.initials: SD
authors.lastname: Barchéchath
authors.forename: Rommel I
authors.initials: RI
authors.lastname: Tawatao
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carson
authors.forename: Howard B
authors.initials: HB
authors.lastname: Cottam
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles; D003907:Dexamethasone / Q000494:pharmacology; D005720:Gamma Rays; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology; D014050:Toluene / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: C505561:2-(2-imino-4,5,6,7-tetrahydrobenzothiazol-3-yl)-1-(4-pyrrolidin-1-ylphenyl)ethanone; C505562:2-(4-pyrrolidin-1-ylphenyl)benzo(d)imidazo(2,1-b)thiazole; D001562:Benzimidazoles; D052160:Benzothiazoles; D007093:Imidazoles; D011759:Pyrrolidines; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D003907:Dexamethasone; C121565:pifithrin