[3 + 2] Cycloaddition with photogenerated azomethine ylides in ß-cyclodextrin.

Stability constants for the inclusion complexes of cyclohexylphthalimide 2 and adamantylphthalimide 3 with ß-cyclodextrin (ß-CD) were determined by 1H NMR titration, K = 190 ± 50 M-1, and K = 2600 ± 600 M-1, respectively. Photochemical reactivity of the inclusion complexes 2@ß-CD and 3@ß-CD was investigated, and we found out that ß-CD does not affect the decarboxylation efficiency, while it affects the subsequent photochemical H-abstraction, resulting in different product distribution upon irradiation in the presence of ß-CD. The formation of ternary complexes with acrylonitrile (AN) and 2@ß-CD or 3@ß-CD was also essayed by 1H NMR. Although the formation of such complexes was suggested, stability constants could not be determined. Irradiation of 2@ß-CD in the presence of AN in aqueous solution where cycloadduct 7 was formed highly suggests that decarboxylation and [3 + 2] cycloaddition take place in the ternary complex, whereas such a reactivity from bulky adamantane 3 is less likely. This proof of principle that decarboxylation and cycloaddition can be performed in the ß-CD cavity has a significant importance for the design of new supramolecular systems for the control of photoreactivity.

Substituted adamantylphthalimides: Synthesis, antiviral and antiproliferative activity.

In this study, three groups of adamantylphthalimides, bearing different substituents at the phthalimide moiety, N-(4'-R2 )phthalimidoadamantanes (1-7), 3-[N-(4'-R2 )phthalimido]-1-adamantanols (8-10), and 3-[N-(4'-R2 )phthalimido]adamantane-1-carboxylic acids (11-15), were synthesized and screened against tumor cells and viruses. The most potent compounds are not substituted at the adamantane and bear an OH or NH2 substituent at the phthalimide (compounds 3 and 5). The antiproliferative activities of compounds 3 and 5 are in the micromolar range, much higher than the one of thalidomide. A minor antiviral activity against cytomegalovirus and varicella-zoster virus was found for compounds 3 and 5, but these compounds lacked selectivity. The results presented are important for the rational design of the next-generation compounds with anticancer and antiviral activities.

Novel coumarin derivatives containing 1,2,4-triazole, 4,5-dicyanoimidazole and purine moieties: synthesis and evaluation of their cytostatic activity.

We report here on the synthesis and in vitro anti-tumor effects of a series of novel 1,2,4-triazole (compounds 3-6), 4,5-dicyanoimidazole (compound 7), and purine (compounds 8-13) coumarin derivatives and their acyclic nucleoside analogues 14-18. Structures of novel compounds 3-18 were deduced from their (1)H- and (13)C-NMR and corresponding mass spectra. Results of anti-proliferative assays performed on a panel of selected human tumor cell lines revealed that compound 6 had moderate cytostatic activity against the HeLa cell line (IC(50) = 35 µM), whereas compound 10 showed moderate activity against the HeLa (IC(50) = 33 µM), HepG2 (IC(50) = 25 µM) and SW620 (IC(50) = 35 µM) cell lines. These compounds showed no cytotoxic effects on normal (diploid) human fibroblasts.

Novel 1,2,4-triazole and purine acyclic cyclopropane nucleoside analogues: synthesis, antiviral and cytostatic activity evaluations.

BACKGROUND: Several published studies indicate that the acyclic guanine nucleoside analogues possessing bis(1,2-hydroxymethyl) substituted cyclopropane rings mimicking the sugar moiety are potent inhibitors of replication of several herpes viruses. METHODS: Established synthetic methods and antiviral and cytostatic activity assays were used for the evaluation of new 1,2,4-triazole and purine acyclic nucleoside analogues. RESULTS: The synthesis of new types of acyclic nucleoside analogues which incorporate 1,2,4-triazole or purine moiety bound via flexible methylenic spacer to the bis(1,2-hydroxymethyl) cyclopropane ring. None of the new compounds showed pronounced antiviral activities at subtoxic concentrations on a broad panel of DNA and RNA viruses. Evaluation of their affinity for herpes simplex type 1 (HSV-1) and varicella-zoster virus-encoded thymidine kinases (VZV TK) also showed that none of the compounds was able to significantly inhibit 1 µM deoxythymidine phosphorylation by HSV-1 and VZV TK at 500 µM concentrations. The in vitro cytostatic activity evaluation results indicated a weak antiproliferative activity for all tested compounds. Only 6-pyrrolylpurine derivative bearing a carboxylic group substituted cyclopropane ring produced a rather slight inhibitory effect at higher micromolar concentrations on a breast carcinoma cell line (MCF-7) and no cytotoxic effect on human normal fibroblasts (WI 38). CONCLUSIONS: The lack of antiherpetic activity may be due to poor, if any, recognition of the compounds by virus-induced nucleoside kinases as an alternative substrate to become metabolically activated.