Anthracyclines are
effective drugs in the treatment of various
cancers, but their use comes with severe side effects. The archetypal
anthracycline drug, doxorubicin, displays two molecular modes of action:
DNA double-strand break formation (through topoisomerase IIα
poisoning) and chromatin damage (via eviction of histones). These
biological activities can be modulated and toxic side effects can
be reduced by separating these two modes of action through alteration
of the aminoglycoside moiety of doxorubicin. We herein report on the
design, synthesis, and evaluation of a coherent set of configurational
doxorubicin analogues featuring all possible stereoisomers of the
1,2-amino-alcohol characteristic for the doxorubicin 3-amino-2,3-dideoxyfucoside,
each in nonsubstituted and N,N-dimethylated forms. The set of doxorubicin
analogues was synthesized using appropriately protected 2,3,6-dideoxy-3-amino
glycosyl donors, equipped with an alkynylbenzoate anomeric leaving
group, and the doxorubicin aglycon acceptor. The majority of these
glycosylations proceeded in a highly stereoselective manner to provide
the desired axial α-linkage. We show that both stereochemistry
of the 3-amine carbon and N-substitution state are critical for anthracycline
cytotoxicity and generally improve cellular uptake.
N
,
N
-Dimethylepirubicin is identified as the most
potent anthracycline that does not induce DNA damage while remaining
cytotoxic.
We
report the practical, scalable synthesis of a range of N-methyl allylic amines. Primary and secondary allylic alcohols
underwent a regioselective Mitsunobu reaction with readily accessible N-Boc ethyl oxamate to deliver the corresponding N-Boc allylic amines, including in enantiopure form via
stereospecific substitution. Subsequent N-methylation
and Boc deprotection without chromatography yielded the amine products
as hydrochloride salts. This method solves the problem of converting
commercially available alcohols into often volatile N-methyl allylic amines, many of which have limited commercial availability.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.