A growth-differentiation factor 15 receptor agonist in randomized placebo-controlled trials in healthy or obese persons.

Background: Growth Differentiation Factor 15 (GDF15), a divergent member of the TGF-β superfamily, signals via the hindbrain glial-derived neurotrophic factor receptor alpha-like and rearranged during transfection receptor co-receptor (GFRAL-RET) complex. In nonclinical species, GDF15 is a potent anorexigen leading to substantial weight loss. MBL949 is a half-life extended recombinant human GDF15 dimer.

Homolog of tocopherol C methyltransferases catalyzes N methylation in anticancer alkaloid biosynthesis.

Madagascar periwinkle (Catharanthus roseus) is the sole source of the anticancer drugs vinblastine and vincristine, bisindole alkaloids derived from the dimerization of the terpenoid indole alkaloids vindoline and catharanthine. Full elucidation of the biosynthetic pathways of these compounds is a prerequisite for metabolic engineering efforts that will improve production of these costly molecules. However, despite the medical and commercial importance of these natural products, the biosynthetic pathways remain poorly understood.

Biocatalytic asymmetric formation of tetrahydro-β-carbolines.

Strictosidine synthase triggers the formation of strictosidine from tryptamine and secologanin, thereby generating a carbon-carbon bond and a new stereogenic center. Strictosidine contains a tetrahydro-β-carboline moiety - an important N-heterocyclic framework found in a range of natural products and synthetic pharmaceuticals. Stereoselective methods to produce tetrahydro-β-carboline enantiomers are greatly valued.

Mechanistic advances in plant natural product enzymes.

The biosynthetic pathways of plant natural products offer an abundance of knowledge to scientists in many fields. Synthetic chemists can be inspired by the synthetic strategies that nature uses to construct these compounds. Chemical and biological engineers are working to reprogram these biosynthetic pathways to more efficiently produce valuable products.

'Novel alkyl side chain sulfone 1alpha,25-dihydroxyvitamin D3 analogs: a comparison of in vitro antiproliferative activities and in vivo calcemic activities'.

The replacement of a t-butyl group with a trifluoromethyl group has profound effects on the biological profile of 1alpha,25-dihydroxyvitamin D(3) sulfone analogs. Investigation of whether the improved biological activities are due to steric and electronic factors of the trifluoromethyl group led to the design, synthesis and biological evaluation of two analogous alkyl sulfone molecules, methyl sulfone (AU-16-ene-25-SO(2)-CH(3)) and isopropyl sulfone (AU-16-ene-25-SO(2)-i-Pr). These alkyl sulfones are sterically comparable to, but electronically very different from a trifluoromethyl group.

Malaria-infected mice are cured by oral administration of new artemisinin derivatives.

In four or five chemical steps from the 1,2,4-trioxane artemisinin, a new series of 23 trioxane dimers has been prepared. Eleven of these new trioxane dimers cure malaria-infected mice via oral dosing at 3 x 30 mg/kg. The clinically used trioxane drug sodium artesunate prolonged mouse average survival to 7.

Antiproliferative, low-calcemic, fluorinated sulfone analogs of 1alpha,25-dihydroxyvitamin D3: chemical synthesis and biological evaluation.

Novel fluorinated sulfone analogs of the hormone 1alpha,25-dihydroxyvitamin D(3) have been designed and synthesized in order to study the biological effects of fluorine incorporation at the terminus of the C,D-ring side chain. Although biologically active 26,27-hexafluorinated 1alpha,25-dihydroxyvitamin D(3) analogs have been synthesized previously, this investigation reports the first successful fluorinated series in which trifluoromethyl sulfone analogs present a favorable biological profile. This study shows that two new analogs featuring incorporation of a synthetically simple single trifluoromethyl sulfone group have significantly increased antiproliferative activity while causing desirably low in vivo calciuria relative to that of calcitriol.

Unexpected steric effects of "remote" alkyl groups on the rate of conjugate additions to alkyl alpha,beta-ethylenic sulfones, sulfoxides, and esters.

Examination of conjugated ethylenic sulfones, sulfoxides, and esters in Michael-type addition reactions reveals, for the first time, that the size of the heteroatom-attached alkyl group affects the rate of conjugate addition. Molecular modeling strongly suggests that what are generally considered to be "remote" alkyl groups in -CbetaH=CalphaHS(O)n-alkyl systems and -CH2CbetaH=CalphaHCOO-alkyl systems are actually not remote from the beta-carbon atom of the Michael accepting unit. Molecular modeling clearly shows that the alkyl groups in these Michael acceptors shield the beta-carbons in the following order: Et View Article and Find Full Text PDF