Synthesis of taxoids with improved cytotoxicity and solubility for use in tumor-specific delivery.
To develop effective taxane-antibody immunoconjugates, we have prepared a series of modified taxanes that have both improved toxicity and solubility in aqueous systems as compared to paclitaxel (1a). These taxanes have been modified at either the C-10 or C-7 position and were found to be very cytotoxic against both normal and multi-drug-resistant (MDR) cells, as well as up to 30 times more soluble than paclitaxel in various buffer systems.
Miller
Michael L
ML
ImmunoGen, Inc., 128 Sidney Street, Cambridge, Massachussetts 02139, USA.
Roller
Elizabeth E
EE
Zhao
Robert Y
RY
Leece
Barbara A
BA
Ab
Olga
O
Baloglu
Erkan
E
Goldmacher
Victor S
VS
Chari
Ravi V J
RV
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D001671:Biochemistry / Q000379:methods; D001943:Breast Neoplasms / Q000188:drug therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D004220:Disulfides / Q000737:chemistry; D004337:Drug Carriers; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C492673:12b-acetyloxy-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,11-dihydroxy-12-(2,5-dimethoxybenzyloxy)-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca(3,4)benz(1,2-b)oxet-9-yl 3-(tert-butyloxycarbonyl)amino-2-hydroxy-5-methyl-4-hexaenoate; D000970:Antineoplastic Agents; D004220:Disulfides; D004337:Drug Carriers; D043823:Taxoids; D011092:Polyethylene Glycols; D017239:Paclitaxel