A two-directional strategy for the diversity-oriented synthesis of macrocyclic scaffolds.
Macrocyclic compounds represent a structural class with exceptional potential for biological activity; however, they have historically been underrepresented in screening collections and synthetic libraries. In this article we report the development of a highly step-efficient strategy for the diversity-oriented synthesis of complex macrocyclic architectures, using a modular approach based on the two-directional synthesis of bifunctional linear precursors and their subsequent combination in a two-directional macrocyclisation process. In this proof of principle study, the synthesis of 14 such compounds was achieved. Cheminformatic analysis of the compounds produced suggests that they reside in biologically relevant regions of chemical space and the compounds were screened for activity against two cancer cell lines.
Department of Chemistry, University of Cambridge, Cambridge, UK CB2 1EW.
Kieron M G
KM
O'Connell
Henning S G
HS
Beckmann
Luca
L
Laraia
Helen T
HT
Horsley
Andreas
A
Bender
Ashok R
AR
Venkitaraman
David R
DR
Spring
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000577:Amides; D000970:Antineoplastic Agents; D047028:Macrocyclic Compounds; D008301:Maleimides