Chemoenzymatic Posttranslational Modification Reactions for the Synthesis of Ψ[CH NH]-Containing Peptides.

The Ψ[CH NH] reduced amide bond is a peptide isostere widely used in the development of bioactive pseudopeptides. Reported here is a method of chemoenzymatic posttranslational modification for the synthesis of Ψ[CH NH]-containing peptides converted from ribosomally expressed peptides. The posttranslational conversion composed of an enzymatic cyclodehydration and facile two-step chemical reduction achieves deoxygenation of a specific amide bond present in a nonprotected peptide in water.

One-pot synthesis of azoline-containing peptides in a cell-free translation system integrated with a posttranslational cyclodehydratase.

Azoline moieties in the backbones of peptidic natural products are important structural motifs that contribute to diverse bioactivities. Some azoline-containing peptides (Az-peptides) are produced from ribosomally synthesized precursor peptides, in which cysteine, serine, and threonine residues are converted to their corresponding azolines by posttranslational modification through a cyclodehydratase. We have devised an in vitro biosynthesis system of Az-peptides, referred to as the FIT-PatD (flexible in vitro translation) system, by the integration of a cell-free translation system with the posttranslational cyclodehydratase PatD.

Systemic delivery systems of angiogenic gene by novel bubble liposomes containing cationic lipid and ultrasound exposure.

Recently, we developed polyethyleneglycol (PEG)-modified liposomes (Bubble liposomes; BLs) entrapping ultrasound (US) gas and reported that the combination of BL and US exposure was an effective tool for the delivery of pDNA directly into skeletal muscles of an ischemic hindlimb model with local injection. To achieve gene delivery to deeper tissues, we attempted to prepare novel Bubble liposomes which were able to be loaded with pDNA and useful for systemic injection. We prepared BLs using cationic lipid and analyzed the interaction with the BLs and pDNA using flow cytometry.

Efficient siRNA delivery using novel siRNA-loaded Bubble liposomes and ultrasound.

Recently, we developed novel polyethyleneglycol (PEG)-modified liposomes (Bubble liposomes; BLs) entrapping an ultrasound (US) imaging gas and reported that the combination of BLs and US was useful for the delivery of siRNA directly into the cytoplasm. However, the results were obtained using a mixture of BLs and naked siRNA. With systemic injections, it is important to control the biodistribution of both BLs and siRNA.

Design and evaluation of new antipsoriatic antedrug candidates having 16-en-22-oxa-vitamin D3 structures.

Design, synthesis, and in vitro and in vivo evaluation of a series of antipsoriatic antedrugs having 16-en-22-oxa-vitamin D3 are described. Among the seven compounds examined, two are promising: ester 5c and amide 5f, both of which exhibit greater potent antiproliferation activity with lessened calcemic activity than the presently prescribed maxacalcitol (2).

Novel vitamin D3 antipsoriatic antedrugs: 16-En-22-oxa-1alpha,25-(OH)2D3 analogs.

A series of 16-en-22-oxa-derivatives of vitamin D3 based on the structure of maxacalcitol (2) were prepared. Maxacalcitol is currently used topically for the treatment of psoriasis and is recognized as the most successful antedrug of natural vitamin D(3) because it retains the original antiproliferative activity of calcitriol without increased calcemic activity. We introduced 16-olefinic functionality to accelerate the oxidative metabolism of the drug in liver, presumed to be essential for the reduction of calcemic activity, and modified the side-chain moiety by placing the 22-oxygen on the more labile allylic carbon center.

Design and synthesis of 4,6-di-tert-butyl-2,3-dihydro-5-benzofuranols as a novel series of antiatherogenic antioxidants.

Antioxidants have been considered as potential antiatherogenic agents by inhibiting oxidation of low-density lipoprotein (LDL), albeit vitamin E, a natural antioxidant, has failed to show reduction on atherosclerosis in clinical trials. We have rationally designed and synthesized a novel series of antioxidants, 4,6-di-tert-butyl-2,3-dihydro-5-benzofuranols, to overcome the clinical limitation of vitamin E. In vitro, the compounds showed a potent inhibitory effect on lipid peroxidation detected as 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyrazin-3-one (MCLA)-dependent chemiluminescence in linoleic acid autoxidation.