Structure-activity relationships of ring C-secotaxoids. 1. Acylative modifications.
The acylative modification of IDN 5390 (3a), a 7,8-secotaxoid under preclinical development, was investigated. A modest decrease of potency was observed upon acylation of the primary and the enolic hydroxyls, suggesting that, just like in paclitaxel, the hydroxyl groups in the upper right-hand sector are not critical for cytotoxicity. The activity of these analogues, and especially of the chemically robust carbonates 3c and 3d, makes it unlikely that the activity of IDN 5390 is due to in vivo oxidation to a fledgling 7-aldehyde and re-aldolization to the corresponding taxane derivative.
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Viale Ferrucci 33, 28100 Novara, Italy.
Giovanni
G
Appendino
Piergiorgio
P
Bettoni
Alain
A
Noncovich
Olov
O
Sterner
Gabriele
G
Fontana
Ezio
E
Bombardelli
Paula
P
Pera
Ralph J
RJ
Bernacki
D000215:Acylation; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000737:chemistry* / Q000494:pharmacology*; D003500:Cyclization; D018432:Drug Resistance, Multiple / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C483639:9-acetyl IDN 5390; D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; C459840:IDN 5390; D043823:Taxoids