151923-86-3Relevant academic research and scientific papers
Toward aplyronine payloads for antibody-drug conjugates: Total synthesis of aplyronines A and D
An?i?ek, Nika,Williams, Simon,Housden, Michael P.,Paterson, Ian
, p. 1343 - 1350 (2018/03/06)
The aplyronines are a family of antimitotic marine macrolides that disrupt cytoskeletal dynamics by dual targeting of both actin and tubulin. Given their picomolar cytotoxicity profile and unprecedented mode of action, the aplyronines represent an excellent candidate as a novel payload for the development of next-generation antibody-drug conjugates (ADCs) for cancer chemotherapy. Enabled by an improved second-generation synthesis of the macrolactone core 5, we have achieved the first total synthesis of the most potent congener aplyronine D together with a highly stereocontrolled synthesis of aplyronine A. To facilitate step economy, an adventurous site-selective esterification of the C7 hydroxyl group was performed to install the N,N,O-trimethylserine pharmacophore to directly afford aplyronines A and D. Toward the assembly of ADCs incorporating an aplyronine warhead, the C29-ester derivative 4 featuring an Fmoc-amino substituted linker attached to the actin-binding tail region was also prepared by adapting this flexible endgame.
Total synthesis of aplyronine C
Paterson, Ian,Fink, Sarah J.,Lee, Lydia Y. W.,Atkinson, Stephen J.,Blakey, Simon B.
supporting information, p. 3118 - 3121 (2013/07/26)
A highly stereocontrolled total synthesis of the cytotoxic marine macrolide aplyronine C is described. The route exploits aldol methodology to install the requisite stereochemistry and features a crucial boron-mediated aldol coupling of an N-vinylformamide-bearing methyl ketone with a macrocyclic aldehyde to introduce the full side chain. The synthesis of two novel C21-C34 side chain analogs is also reported.
