Osteopontin (OPN) Downregulatory Alkaloid (-)-Agelastatin A Prevents Muscle Damage in a Mouse Model of Duchenne Muscular Dystrophy

<p>(-)-Agelastatin A (AA) in 1,2-propanediol (3-deoxy-DL-glycerol) elicits a dose-dependent decrease in OPN mRNA expression in canine Duchenne Muscular Dystrophy (DMD) myoblasts at doses ranging from 0.01 nM-30 nM. When intraperitoneally administered in the same vehicle to mdx mice at 2.5 mg/kg/day for two weeks, and at 1.5 mg/kg/day twice-weekly for two weeks, (-)-AA brings about a significant decrease in exercise-induced muscle damage through its attenuation of OPN expression. Because (-)-AA is known to downregulate OPN, this study confirms that the use of small molecule OPN downregulatory drugs can beneficially modify the phenotype in DMD animal models and potentially affected boys</p>

Osteopontin (OPN) Downregulatory Alkaloid (-)-Agelastatin A Prevents Muscle Damage in a Mouse Model of Duchenne Muscular Dystrophy

<p>(-)-Agelastatin A (AA) in 1,2-propanediol (3-deoxy-DL-glycerol) elicits a dose-dependent decrease in OPN mRNA expression in canine Duchenne Muscular Dystrophy (DMD) myoblasts at doses ranging from 0.01 nM-30 nM. When intraperitoneally administered in the same vehicle to mdx mice at 2.5 mg/kg/day for two weeks, and at 1.5 mg/kg/day twice-weekly for two weeks, (-)-AA brings about a significant decrease in exercise-induced muscle damage through its attenuation of OPN expression. Because (-)-AA is known to downregulate OPN, this study confirms that the use of small molecule OPN downregulatory drugs can beneficially modify the phenotype in DMD animal models and potentially affected boys</p>

A Virtual Screening Platform Identifies Chloroethylagelastatin A as a Potential Ribosomal Inhibitor

Chloroethylagelastatin A (CEAA) is an analogue of agelastatin A (AA), a natural alkaloid derived from a marine sponge. It is under development for therapeutic use against brain tumors as it has excellent central nervous system (CNS) penetration and pre-clinical therapeutic activity against brain tumors. Recently, AA was shown to inhibit protein synthesis by binding to the ribosomal A-site. In this study, we developed a novel virtual screening platform to perform a comprehensive screening of various AA analogues showing that AA analogues with proven therapeutic activity including CEAA have significant ribosomal binding capacity whereas therapeutically inactive analogues show poor ribosomal binding and revealing structural fingerprint features essential for drug-ribosome interactions. In particular, CEAA was found to have greater ribosomal binding capacity than AA. Biological tests showed that CEAA binds the ribosome and contributes to protein synthesis inhibition. Our findings suggest that CEAA may possess ribosomal inhibitor activity and that our virtual screening platform may be a useful tool in discovery and development of novel ribosomal inhibitors.

Total synthesis of (−)-agelastatin A: an SH2′ radical azidation strategy

A new synthetic approach to (−)-agelastatin A has been established through the strategic implementation of brominative olefin transposition of a silyl enol ether and subsequent SH2′ radical azidation of the resultant allylic bromide.

Other Methods for C–C Ring Construction: Pinolinone (Bach), Agelastatin A (Batey), Panaginsene (Lee), Salvileucalin D, Salvileucalin C (Ding), ent-Codeine (Hudlicky), Walsucochin B (Xie/Shi)

Thorsten Bach of the Technische Universität München used (Chem. Commun. 2014, 50, 3353) the chiral medium-mediated photochemical 2+2 cycloaddition that he devel­oped to prepare 3 by combining 1 with 2. Oxidative cleavage led to (−)-pinolinone 4. Robert A. Batey of the University of Toronto rearranged (Angew. Chem. Int. Ed. 2013, 52, 10862) furfural 5 in the presence of 6 to give the enone 7. Acylation fol­lowed by intramolecular conjugate addition delivered agelastatin A 8. Hee-Yoon Lee of KAIST prepared (Org. Lett. 2014, 16, 2466) the tosylhydrazone Na salt 9 from citronellal. Thermolysis led, via a dialkyl diazo intermediate, to the tricy­clic 10. Direct comparison of synthetic material with the natural product panaginsene 11 enabled the assignment of the relative configuration of the pendant methyl group. Hanfeng Ding of Zhejiang University eliminated (Org. Lett. 2014, 16, 3376) HBr from 12 to give, after rearrangement, the cycloheptadiene salvileucalin D 13. Irradiation converted 13 to the cyclobutene salvileucalin C 14. In a recent chapter of his continuing work on the morphine alkaloids, Tomas Hudlicky of Brock University described (Adv. Synth. Catal. 2014, 356, 333) the intra­molecular [3+2] cycloaddition of the nitrone derived from 15 to give 16. This was readily carried on to ent-codeine 17. Xingang Xie and Xuegong She of Lanzhou University used (Org. Lett. 2014, 16, 1996) Shi epoxidation and Itsuno–Corey reduction to prepare 18 in enantiomerically-pure form. Cationic cyclization converted 18 to 19, that was oxidized to (−)-walsucochin B 20.