Glycosylation is an accepted strategy to improve the therapeutic value of peptide and protein drugs. Insulin and its analogues are life-saving drugs for all type I and 30% of type II diabetic patients. However, they can readily form fibrils which is a significant problem especially for their use in insulin pumps. Because of the solubilizing and hydration effects of sugars, it was thought that glycosylation of insulin could inhibit fibril formation and lead to a more stable formulation. Since enzymatic glycosylation results in heterogeneous products, we developed a novel chemical strategy to produce a homogeneous glycoinsulin (disialo-glycoinsulin) in excellent yield (∼60%). It showed a near-native binding affinity for insulin receptors A and B in vitro and high glucose-lowering effects in vivo, irrespective of the route of administration (s.c. vs i.p.). The glycoinsulin retained insulin-like helical structure and exhibited improved stability in human serum. Importantly, our disialo-glycoinsulin analogue does not form fibrils at both high concentration and temperature. Therefore, it is an excellent candidate for clinical use in insulin pumps.

Am ild and efficientp alladium-catalyzed synthetic method for the C À Hf unctionalization of N-(quinolin-8-yl)ferrocenecarboxamide has been developed. Va rious aryl iodides containingI ,N O 2 ,C N, COMe,C O 2 Et, and NH functionalities and also alkyl iodidesu nderwent the Pd-catalyzed intermolecular carbon-carbon bond forming reactionw ith ferrocenecarboxamide successfully which led to ad iverse array of bis(aryl/alkyl)ferrocenecarboxamidesi n3 4-92% yields.C ross-coupling of the ferrocenylC À H bond with aryl iodidesc an also be achieved utilizing an economical Ni catalyst. Additionally,s elective monoalkylation of ferrocenecarboxamide was studied using sodium bicarbonatea sb ase and dibenzylphosphoric acid as additive under Pd-catalyzed reaction conditions.S ubsequently,r emoval of the directing group,8 -aminoquinoline,f rom bis(aryl)ferrocenecarboxamides led to bis(aryl)ferrocenesb earing versatilem ethyl ester andc arboxaldehyde functional groups.Scheme 2. Substrate scope with regard to aryl/heteroaryl iodides.U nlesso therwises tated, isolated yields using 10 mol% of Pd(OAc) 2 in toluene are given.

Insulin-like peptide 5 (INSL5), the natural ligand for the relaxin family peptide receptor 4 (RXFP4), is a gut hormone that is exclusively produced by colonic L-cells. We have recently developed an analogue of INSL5, INSL5-A13, that acts as an RXFP4 agonist in vitro and stimulates colorectal propulsion in wild-type mice but not in RXFP4-knockout mice. These results suggest that INSL5 may have a physiological role in the control of colorectal motility. To investigate this possibility, in this study we designed and developed a novel INSL5 analogue, INSL5-A13NR. This compound is a potent antagonist, without significant agonist activity, in two in vitro assays. We report here for the first time that this novel antagonist peptide blocks agonist-induced increase in colon motility in mice that express RXFP4. Our data also show that colorectal propulsion induced by intracolonic administration of bacterial products (short-chain fatty acids, SCFAs) is antagonized by INSL5-A13NR. Therefore, INSL5-A13NR is an important research tool and potential drug lead for the treatment of colon motility disorders, such as bacterial diarrheas.

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