Synthesis of paromomycin derivatives modified at C(5'') to selectively target bacterial rRNA.
The furanosyl moiety (ring III) of C(6')-deoxyparomomycin and paromomycin was modified in search of aminoglycoside antibiotics with altered selectivity. The key intermediates were the N-Boc-protected derivative of C(6')-deoxyparomomycin and the benzylidene-protected paromomycin. Their H(2)C(5'')-OH group was oxidised with trichlorocyanuric acid or [bis(acetoxy)iodo]benzene in the presence of catalytic amounts of TEMPO to yield the corresponding aldehydes and acids, which were transformed into the protected alkoxy imines, amides and the amine. Standard deprotection gave the title compounds derived from C(6')-deoxyparomomycin and derived from paromomycin that proved less active than paromomycin and its C(6')-deoxy analogue.
Kudyba
Iwona
I
Laboratorium für Organische Chemie, ETH Zürich, HCI, CH-8093 Zürich, Switzerland.
Fernandez
Déborah Perez
DP
Böttger
Erik C
EC
Vasella
Andrea
A
D020102:Mycobacterium smegmatis / Q000187:drug effects; D010084:Oxidation-Reduction; D010303:Paromomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D012329:RNA, Bacterial / Q000737:chemistry*; D012335:RNA, Ribosomal / Q000737:chemistry*; D012270:Ribosomes / Q000187:drug effects; D013329:Structure-Activity Relationship
D012329:RNA, Bacterial; D012335:RNA, Ribosomal; D010303:Paromomycin