A series of isomeric 4-[[3-(dimethylamino)propyl]amino]nitroquinolines has been synthesized and evaluated as hypoxia-selective cytotoxins and as radiosensitizers of hypoxic cells. The compounds showed widely-differing hypersensitivity factors (ratios of cytotoxicity against wild-type and repair-deficient mammalian cells). Many compounds showed oxygen-sensitive bioreduction resulting in DNA alkylation, while others show oxygen-insensitive modes of action. Of the nitro isomers studied, the 5-nitro showed the greatest hypoxic selectivity. A series of ring-substituted analogues were then prepared, in an effort to lower its reduction potential of -286 mV. Structure-activity studies showed that the effects of substitution on reduction potential were complex, being mediated by electronic and steric effects on the nitro group, as well as by effects on quinoline pKa. Two compounds of lower reduction potential, the 3- and 8-methyl analogues, showed improved selectivity (47- and 60-fold in a clonogenic assay). These two compounds also showed the highest "in vitro therapeutic indices" of the series as hypoxic cell radiosensitizers. Despite these favorable in vitro properties, neither compound had activity against hypoxic cells in SCCVII tumors when administered at 60% of the MTD.

. LOCK. Can. J. Chem. 64,943 (1986). Fastigiatine, C19H28N20, is a minor component of the alkaloids of Lycopodium fastigiatum R. Br. collected in New Zealand.Its structure and relative configuration have been resolved by an X-ray analysis of the free base. The pentacyclic ring system of fastigiatine has not been previously observed in the Lycopodium family of alkaloids or elsewhere. A proposal is presented for its derivation from the tetracyclic flabellidane ring system that is widely distributed among Lycopodium species. The mass spectrum and the 13c and 'H nrnr spectra of fastigiatine are discussed.ROBERT V. GERARD, DAVID B. MACLEAN, ROMOLO FAGIANN~, et COLIN J. LOCK. Can. J. Chem. 64, 943 (1986). La fastigiatine, C19H28N20, est un constituant mineur des alcalo'ides du Lycopodium fastigiatine R. Br. rtcoltt en Nouvelle Zlande. On a rtsolu sa structure et sa configuration relative par I'analyse aux rayons-X de la base libre. On n'avait pas encore observt le systtme pentacyclique de la fastigiatine dans la farnille des alcalo~des du Lycopodium ou ailleurs. On propose une mtthode de prtpariition de la fastigiatine h partir du systkme tttracyclique de la flabellidane que I'on retrouve souvent dans les espkes du Lycopodium. On discute du spectre de masse et des spectres rmn du I3c et du 'H de la fastigiatine.[Traduit par la revue]

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. Can. J. Chem. 72, 382 (1994).The structure of azapropazone, 5-(dimethylamino)-9-methyl-2-propyl-1 H-pyrazolo[l,2-a][] ,2,4]benzotriazine-1,3(2H)-dione, was determined by single crystal X-ray diffraction. Crystals were orthorhombic (P212121), with a = 5.570(1) A, b = 14.593(3) A, c = 19.270(4) A, and Z = 4. Intensities were measured on a Rigaku AFC6-R diffractometer with Cu-Ka radiation and 23 16 reflections were used to determine the structure. Contrary to previous postulates, the tricyclic portion of the molecule is not planar. Azapropazone is a zwitterion with the negative charge delocalized over the P-keto-en01 system and with the proton on N(6) of the triazine ring. The nonplanarity of the molecule is caused by steric interaction of a methyl group on the exocyclic dimethylamino group with O(3) of the keto-en01 system. Bond lengths and angles are normal. NMR studies showed that at room temperature rapid inversion occurs between the two enantiomers, but this inversion slows at low temperatures with A@ = 44.9(2) kJ mol-I. The product derived from opening of the pyrazolidine ring of azapropazone by formic acid is not as previously formulated. The compound is 3-dimethylamino-7-methyl-l-valeryl-l,4-dihydro-l,2,4-benzotriazine. Its structure was determined by single crystal X-ray diffraction. Crystals were monoclinic (P21/r~), with a = 10.240(2) A, b = 12.608(3) A, c = 13.176(3) A, P = 108.46(3)", and Z = 4. Intensities were measured on a Rigaku AFC6-R diffractometer with Cu-Ka radiation and 2209 reflections were used to determine the structure. The conformation of the benzotriazine ring system was very similar to that observed in azapropazone and bond lengths and angles were normal. Cu et on a utilisC 2316 reflexions pour determiner la structure. Contrairement aux postulats antkrieurs, la portion tricyclique de la molCcule n'est pas plane. L'azapropazone est un zwitterion avec une charge negative dClocalisCe sur le systbme P-cCto-Cnolique et avec le proton sur le N(6) du noyau triazine. Le caractbre non-planaire de la molecule est provoquC par une interaction stCrique du groupe mCthyle port6 par le groupe dimCthylamino exocyclique avec le O(3) du systbme cCto-Cnolique. Les longueurs des liaisons et les angles sont normaux. Les Ctudes de RMN ont montrC que, a la temperature ambiante, il se produit une interconversion rapide entre les deux Cnantiombres, mais que l'inversion est ralentie basse tempkrature avec un A@ = 44,9(2) kJ mol-l. Le produit obtenu par ouverture du noyau pyrazolidine de l'azapropazone par l'acide formique ne correspond pas a celui qui avait kt6 formulC antkrieurement. Le composC est le 3-dimCthylamino-7-mCthyl-1-valCryl-l,4-dihydro-l,2,4-benzotriazine, On a dCterminC la structure par diffraction des rayons X par un cristal unique. Les cristaux sont monocliniques (P21/t1), avec a = 10,240(2) A, b = 12,608(3) A, c = 13,176(3) A, P = 108,46(3)" et Z = 4. On a mesurC les intensites l'aide d'un diffractombtre Rigaku AFC6-R, avec le rayonnement K a du Cu et on a utilisC 2209 rkflexions pour determi...