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Intermediates O 0190Generation and Reaction of Ammonium Ylides in Basic Two-Phase Systems -The reaction of ammonium ylides, generated from quaternary ammonium salts (I) under alkaline conditions with various electrophilic agents is studied. Thus, reaction with alkenes (II) and (V) provides access towards cyclopropane derivatives (III)/(IV) and (VI), resp., in good yields, the cis-trans selectivity being determined by the substrate structure. Reaction with alkyl halides (VII) gives cyanoalkenes (VIII). When allylation agents like (VIIa) are used, the cyclopropanation of the γ,δ-double bond [cf. (IX)] is possible by change of the substrate ratio. The reaction of ammonium ylides with aldehydes (XI) gives cyanooxiranes with good to excellent cis-selectivity. -(KOWALKOWSKA, A.; SUCHOLBIAK, D.; JONCZYK*, A.; Eur. J. Org. Chem. 2005, 5, 925-933; Fac. Chem., Warsaw Univ. Technol., PL-00-662 Warszawa, Pol.; Eng.) -Mischke 27-046

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Enzymes involved in thymidylate biosynthesis, thymidylate synthase (TS), and dihydrofolate reductase (DHFR) are well-known targets in cancer chemotherapy. In this study, we demonstrated for the first time, that human TS and DHFR form a strong complex in vitro and co-localize in human normal and colon cancer cell cytoplasm and nucleus. Treatment of cancer cells with methotrexate or 5-fluorouracil did not affect the distribution of either enzyme within the cells. However, 5-FU, but not MTX, lowered the presence of DHFR-TS complex in the nucleus by 2.5-fold. The results may suggest the sequestering of TS by FdUMP in the cytoplasm and thereby affecting the translocation of DHFR-TS complex to the nucleus. Providing a strong likelihood of DHFR-TS complex formation in vivo, the latter complex is a potential new drug target in cancer therapy. In this paper, known 3D structures of human TS and human DHFR, and some protozoan bifunctional DHFR-TS structures as templates, are used to build an in silico model of human DHFR-TS complex structure, consisting of one TS dimer and two DHFR monomers. This complex structure may serve as an initial 3D drug target model for prospective inhibitors targeting interfaces between the DHFR and TS enzymes.