6688-71-7Relevant academic research and scientific papers
Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Investigations
Nicolaou,Wang, Yanping,Lu, Min,Mandal, Debashis,Pattanayak, Manas R.,Yu, Ruocheng,Shah, Akshay A.,Chen, Jason S.,Zhang, Hongjun,Crawford, James J.,Pasunoori, Laxman,Poudel, Yam B.,Chowdari, Naidu S.,Pan, Chin,Nazeer, Ayesha,Gangwar, Sanjeev,Vite, Gregory,Pitsinos, Emmanuel N.
supporting information, p. 8235 - 8246 (2016/07/15)
From the enediyne class of antitumor antibiotics, uncialamycin is among the rarest and most potent, yet one of the structurally simpler, making it attractive for chemical synthesis and potential applications in biology and medicine. In this article we describe a streamlined and practical enantioselective total synthesis of uncialamycin that is amenable to the synthesis of novel analogues and renders the natural product readily available for biological and drug development studies. Starting from hydroxy- or methoxyisatin, the synthesis features a Noyori enantioselective reduction, a Yamaguchi acetylide-pyridinium coupling, a stereoselective acetylide-aldehyde cyclization, and a newly developed annulation reaction that allows efficient coupling of a cyanophthalide and a p-methoxy semiquinone aminal to forge the anthraquinone moiety of the molecule. Overall, the developed streamlined synthesis proceeds in 22 linear steps (14 chromatographic separations) and 11% overall yield. The developed synthetic strategies and technologies were applied to the synthesis of a series of designed uncialamycin analogues equipped with suitable functional groups for conjugation to antibodies and other delivery systems. Biological evaluation of a select number of these analogues led to the identification of compounds with low picomolar potencies against certain cancer cell lines. These compounds and others like them may serve as powerful payloads for the development of antibody drug conjugates (ADCs) intended for personalized targeted cancer therapy.
DERIVATIVES OF UNCIALAMYCIN, METHODS OF SYNTHESIS AND THEIR USE AS ANTITUMOR AGENTS
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Page/Page column 102; 103, (2015/02/25)
In one aspect, the present disclosure provides new analogs of uncialamycin of formulae (I) and (II). The present disclosure also provides novel synthetic pathways to obtaining uncialamycin and analogs thereof. Additionally, the present disclosure also describes methods of use of uncialamycin and analogs thereof. In another aspect, the present disclosure provides antibody-drug conjugates comprising the compounds of formulae (I) and (ll).
Synthesis of Averufin and its Role in Aflatoxin B1 Biosynthesis
Townsend, Craig A.,Christensen, Siegfried B.,Davis, Steven G.
, p. 839 - 862 (2007/10/02)
Described are two total syntheses of (+/-)-averufin (4) proceeding through a common intermediate and predicated on the efficient introduction of isotopic label(s) at side-chain and nuclear sites for the purpose of biosynthetic investigations of aflatoxin B1 (8).Using these methods, (+/-)--and --averufin, (65) and (68) respectively, and a 1:1 mixture of (+/-)-- and --averufin (71) were prepared and incorporated into aflatoxin B1 using mycelial suspensions of Aspergillus parasiticus (SU-1).In each instance efficient and specific utilization of label was observed in the product by (13)C-n.m.r.spectroscopy, demonstrating the intact incorporation of averufin.When compared with earlier observations of acetate incorporation, a complete correlation of the carbon skeleton from the intermediate anthraquinone stage of the four carbons lost in this overall process were unambiguously identified.In the formation of the dihydrobisfuran, the anthraquinone nucleus migrates to C-2' to branch the linear side-chain of averufin.Deuterium bound at C-1' in averufin is carried to C-13 of aflatoxin.Preparation from (+/-)-averufin (68) of (+/-)--averufin (73) and incorporation of the latter into versiconal acetate (5) demonstrated loss of the terminal two carbons of the averufin side-chain, presumably as acetate, by way of a Baeyer-Villiger-like oxidation.
Depsidone Synthesis. Part 21. A New Synthesis of Grisa-2',5'-diene-3,4'-diones
Sargent, Melvyn V.
, p. 403 - 411 (2007/10/02)
Treatment of suitably substituted methyl 2-phenoxybenzoates with titanium(IV) chloride and dry hydrogen chloride afforded grisa-2',5'-diene-3,4'-diones in high yield.The structures of these compounds followed from their thermal stability, their methanolysis to methyl 2-(4-hydroxyphenoxy)benzoates, and their reductive cleavage to 2,4'-dihydrobenzophenones.Treatment of the benzophenones with base gave xanthones.An attempt to synthesize dehydrogriseofulvin (1) by this method failed.
