Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Investigations.
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.
Department of Chemistry, BioScience Research Collaborative, Rice University , 6100 Main Street, Houston, Texas 77005, United States.|Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
K C
KC
Nicolaou
Department of Chemistry, BioScience Research Collaborative, Rice University , 6100 Main Street, Houston, Texas 77005, United States.
Yanping
Y
Wang
Department of Chemistry, BioScience Research Collaborative, Rice University , 6100 Main Street, Houston, Texas 77005, United States.|Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Min
M
Lu
Department of Chemistry, BioScience Research Collaborative, Rice University , 6100 Main Street, Houston, Texas 77005, United States.|Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Debashis
D
Mandal
Department of Chemistry, BioScience Research Collaborative, Rice University , 6100 Main Street, Houston, Texas 77005, United States.|Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Manas R
MR
Pattanayak
Department of Chemistry, BioScience Research Collaborative, Rice University , 6100 Main Street, Houston, Texas 77005, United States.
Ruocheng
R
Yu
Department of Chemistry, BioScience Research Collaborative, Rice University , 6100 Main Street, Houston, Texas 77005, United States.
Akshay A
AA
Shah
Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Jason S
JS
Chen
Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Hongjun
H
Zhang
Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
James J
JJ
Crawford
Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Laxman
L
Pasunoori
Bristol-Myers Squibb Research & Development , 700 Bay Road, Redwood City, California 94063, United States.
Yam B
YB
Poudel
Bristol-Myers Squibb Research & Development , 700 Bay Road, Redwood City, California 94063, United States.
Naidu S
NS
Chowdari
Bristol-Myers Squibb Research & Development , 700 Bay Road, Redwood City, California 94063, United States.
Chin
C
Pan
Bristol-Myers Squibb Research & Development , 700 Bay Road, Redwood City, California 94063, United States.
Ayesha
A
Nazeer
Bristol-Myers Squibb Research & Development , 700 Bay Road, Redwood City, California 94063, United States.
Sanjeev
S
Gangwar
Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543-4000, United States.
Gregory
G
Vite
Department of Chemistry, BioScience Research Collaborative, Rice University , 6100 Main Street, Houston, Texas 77005, United States.|Laboratory of Natural Products Synthesis & Bioorganic Chemistry, Institute of Nanoscience & Nanotechnology, National Centre of Scientific Research "Demokritos" , Agia Paraskevi GR-15310, Greece.
Emmanuel N
EN
Pitsinos
D000880:Anthraquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D011809:Quinones / Q000737:chemistry; D013329:Structure-Activity Relationship
D000880:Anthraquinones; D000970:Antineoplastic Agents; D011809:Quinones; C512009:uncialamycin