Caspases are responsible for the execution of the cell death program and are potentially suitable targets for the specific imaging of apoptosis in vivo. A series of N-1-substituted analogues of the small molecule nonpeptide caspase inhibitor (S)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (1), which may be useful for the development of caspase-targeted radioligands, were synthesized and their inhibition potencies were evaluated in vitro. Two of the most powerful techniques to introduce fluorine into organic compounds, viz, bromofluorination of olefins and fluorohydrin synthesis by ring-opening of epoxides, were used. Most of the target compounds are potent inhibitors of the two effector caspases-3 and -7. Furthermore, the (18)F-radiolabeled model compound (S)-1-[4-(1-[(18)F]fluoro-2-hydroxyethyl)benzyl]-5-[1-(2-methoxymethyl-pyrrolidinyl)sulfonyl]isatin ([(18)F]37), a putative tracer for the noninvasive imaging of apoptosis by positron emission tomography (PET) was synthesized by nucleophilic epoxide ring-opening of its precursor 36. The radiochemistry utilized in the (18)F-fluorination reverted to carrier-added [(18)F]Et(3)N.3HF, a new fluorine-18 source for radiolabeling.

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Within a series of new mono-, di- and trifluoromethylated pyrrolidine ring analogs of the lead compound, high inhibition potencies were found for caspases-3 and -7 with IC(50) values up to 30 and 37 nM, respectively. A new oxidative desulfurization-fluorination protocol was shown to be a versatile technique for fluorine incorporation.

Attempts to synthesize the antidepressant drug atomoxetine directly by p-TSA-catalyzed reaction between o-cresol and N-methyl-3-phenyl-3-hydroxypropyl amine in toluene at reflux temperature surprisingly resulted in the formation of ortho-substituted phenol derivative. The structure is unambiguously confirmed by single crystal X-ray.

Polyphenylalkane derivatives Q 0720Unusual p-Toluene Sulfonic Acid-Catalyzed Carbon-Carbon Bond Formation.-An unusual C-C bond formation is reported for the reaction of amine (I) with o-cresol (II) in the presence of Tos-OH as catalyst for the first time. The structure of the unexpected product (III) (no yield given) is confirmed by X-ray analysis. -(GOVINDAN, S.; MADDIPATLA, M.; PODICHETTY, A. K.; MACHARLA, P.; NALIVELA, V.; SUNDARAM, V.; MATHAD, V. T.; GHANTA*, M. R.; YALAVARTI, R. K.; Synth. Commun. 35 (2005) 13, 1765-1768; Dep. Res. Dev., Dr. Reddy's Lab. Ltd., Bollaram, Jinnaram 502 325, India; Eng.) -H. Haber 46-088