CuI-Catalyzed Coupling Reactions of 4-Iodopyrazoles and Alcohols: Application toward Withasomnine and Homologs.

The direct 4-alkoxylation of 4-iodo-1-pyrazoles with alcohols was achieved by a CuI-catalyzed coupling protocol. The optimal reaction conditions employed excess alcohol and potassium -butoxide (2 equiv) in the presence of CuI (20 mol%) and 3,4,7,8-tetramethyl-1,10-phenanthroline (20 mol%) at 130 °C for 1 h under microwave irradiation. The present method was efficiently applied to the synthesis of withasomnine and its six- and seven-membered cyclic homologs.

Synthesis of pyrrole-imidazole polyamide seco-1-chloromethyl-5-hydroxy-1,2-dihydro-3h-benz[e]indole conjugates with a vinyl linker recognizing a 7 bp DNA sequence.

Convergent synthetic routes for N-methylpyrrole (P) and N-methylimidazole (I) seco-1-chloromethyl-5-hydroxy-1,2-dihydro-3H-benz[e]indole (CBI) conjugates with a vinyl linker were developed. New hairpin polyamide-seco-CBI conjugates, compounds 16-19, were synthesized, and their DNA sequence-specific alkylating activities were evaluated via high-resolution denaturing gel electrophoresis and high-performance liquid chromatography (HPLC) product analysis. The new synthetic route for PI conjugates with a vinyl linker consisted of the introduction of a vinylpyrrole unit (8-11) into the C terminal of a PI polyamide synthesized by (fluorenylmethoxy)carbonyl solid-phase peptide synthesis (SPPS), followed by liquid-phase coupling with seco-CBI.

Synthesis and biological properties of highly sequence-specific-alkylating N-methylpyrrole-N-methylimidazole polyamide conjugates.

Four new alkylating N-methylpyrrole-N-methylimidazole (PI) polyamide conjugates (1-4) with seven-base-pair (bp) recognition ability were synthesized. Evaluation of their DNA-alkylating activity clearly showed accurate alkylation at match site(s). The cytotoxicities of conjugates 1-4 were determined against six human cancer cell lines, and the effect of these conjugates on the expression levels of the whole human genome in A549 cells were also investigated.

Cysteine cyclic pyrrole-imidazole polyamide for sequence-specific recognition in the DNA minor groove.

Pyrrole-imidazole (PI) polyamides are small DNA-binding molecules that can recognize predetermined DNA sequences with high affinity and specificity. Hairpin PI polyamides have been studied intensively; however, cyclic PI polyamides have received less attention, mainly because of difficulties with their synthesis. Here, we describe a novel cyclization method for producing PI polyamides using cysteine and a chloroacetyl residue.

Evaluation of PI polyamide conjugates with eight-base pair recognition and improvement of the aqueous solubility by PEGylation.

To investigate the effect of elongating base-pair (bp) recognition sequences, we synthesized N-methylpyrrole-N-methylimidazole (PI) polyamide conjugates with eight-bp recognition (3-5). The DNA alkylating activities of conjugates 3-5 were evaluated by high-resolution denaturing polyacrylamide gel electrophoresis with a 208-bp DNA fragment. Conjugates 3-5 showed high alkylating activities at nanomolar concentrations.