189190-88-3Relevant academic research and scientific papers
Synthesis and biological evaluation of novel 3′-difluorovinyl taxoids
Kuznetsova, Larissa,Sun, Liang,Chen, Jin,Zhao, Xianrui,Seitz, Joshua,Das, Manisha,Li, Yuan,Veith, Jean M.,Pera, Paula,Bernacki, Ralph J.,Xia, Shujun,Horwitz, Susan B.,Ojima, Iwao
, p. 177 - 188 (2013/01/13)
A series of 3′-difluorovinyl taxoids with C10 modifications, as well as those with C2 and C10 modifications, were strategically designed to block the metabolism by cytochrome P-450 3A4 enzyme and synthesized. These novel difluorovinyl taxoids were evaluated for their cytotoxicity against drug-sensitive human breast (MCF7), multidrug-resistant (MDR) human ovarian (NCI/ADR), human colon (HT-29) and human pancreatic (PANC-1) cancer cell lines. 3′-Difluorovinyl taxoids exhibit several to 16 times better activity against MCF7, HT-29 and PANC-1 cell lines and up to three orders of magnitude higher potency against NCI/ADR cell line as compared to paclitaxel. Structure-activity relationship study shows the critical importance of the C2 modifications on the activity against MDR cancer cell line, while the C10 modifications have a rather minor effect on the potency with some exceptions. The effect of the C2 modifications on potency against MCF7 cell line increases in the following order: H 3. Among the twenty five 3′-difluorovinyl taxoids evaluated, eight taxoids exhibited less than 100 pM IC50 values against MCF7 cell line. Difluorovinyl taxoids induced GTP-independent tubulin polymerization much faster than paclitaxel. Then, the resulting microtubules were stable to Ca2+-induced depolymerization, indicating strong stabilization of microtubules. Molecular modeling study indicated that a difluorovinyl taxoid binds to β-tubulin in a manner that is consistent with the REDOR-Taxol structure. The difluorovinyl group appears to mimic the isobutenyl group to some extent, but with very different electronic property, which may account for the unique activities of difluorovinyl taxoids.
Syntheses and structure-activity relationships of novel 3′-difluoromethyl and 3′-trifluoromethyl-taxoids
Kuznetsova, Larissa V.,Pepe, Antonella,Ungureanu, Ioana M.,Pera, Paula,Bernacki, Ralph J.,Ojima, Iwao
scheme or table, p. 817 - 828 (2009/04/06)
A series of novel 3′-difluoromethyl-taxoids and 3′-trifluoromethyl-taxoids with modifications at the C2 and C10 positions were synthesized and evaluated for their in vitro cytotoxicities against human breast carcinoma (MCF7-S, MCF7-R, LCC6-WT, LCC6-MDR),
Design, synthesis, and biological evaluation of new-generation taxoids
Ojima, Iwao,Chen, Jin,Sun, Liang,Borella, Christopher P.,Wang, Tao,Miller, Michael L.,Lin, Songnian,Geng, Xudong,Kuznetsova, Larisa,Qu, Chuanxing,Gallager, David,Zhao, Xianrui,Zanardi, Ilaria,Xia, Shujun,Horwitz, Susan B.,Mallen-St. Clair, Jon,Guerriero, Jennifer L.,Bar-Sagi, Dafna,Veith, Jean M.,Pera, Paula,Bernacki, Ralph J.
scheme or table, p. 3203 - 3221 (2009/05/11)
Novel second-generation taxoids with systematic modifications at the C2, C10, and C3′N positions were synthesized and their structure-activity relationships studied. A number of these taxoids exhibited exceptionally high potency against multidrug-resistan
Facile method for synthesizing baccatin III compounds
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Page/Page column 9, (2010/02/14)
A process for synthesizing a C-7 protected baccatin III compound represented by formula (A), which comprises reacting a 10-deacetylbaccatin III compound represented by formula (B) with a protecting agent and an acylating agent in the presence of a secondary amine and a nitrogen-containing compound. Also, a process for synthesizing a C-7 protected 10-deacetylbaccatin III compound represented by formula (C), which comprises reacting a 10-deacetylbaccatin III compound represented by formula (B) with a protecting agent in the presence of a secondary amine and a nitrogen-containing compound. In both processes the nitrogen-containing compound is selected from a nitrogen-containing heterocycle or a trialkylamine. When the nitrogen-containing heterocycle is selected, it may be an unsubstituted or a substituted pyridine or an unsubstituted or a substituted pyrazine. When a trialkylamine is selected, it may be, for example, triethylamine or diisopropylethylamine. wherein PG1 represents the organic residue of the protecting agent, PG2 represents the organic residue of the acylating agent, and R represents a simple or substituted aryl group or a heterocyclic group.
Synthesis of potent taxoids for tumor-specific delivery using monoclonal antibodies
Miller, Michael L.,Roller, Elizabeth E.,Wu, Xinyaun,Leece, Barbara A.,Goldmacher, Victor S.,Chari, Ravi V.J.,Ojima, Iwao
, p. 4079 - 4082 (2007/10/03)
The targeted delivery of taxoids, in the form of taxane-antibody immunoconjugates, requires the preparation of taxoids containing moieties suitable for their conjugation to monoclonal antibodies. A series of taxoids incorporating a disulfide-containing li
Synthesis and structure-activity relationships of new second-generation taxoids
Ojima, Iwao,Wang, Tao,Miller, Michael L.,Lin, Songnian,Borella, Christopher P.,Geng, Xudong,Pera, Paula,Bernacki, Ralph J.
, p. 3423 - 3428 (2007/10/03)
A series of second-generation taxoids bearing a substituent on the C-2-benzoyl group and modifications at C-3'/C-10 positions was synthesized. These taxoids exhibited 2-3 orders of magnitude higher potency than that of paclitaxel against drug-resistant human breast cancer cell lines. It is also noteworthy that three taxoids showed almost no difference in activity against drug-resistant and drug-sensitive cell lines, which are categorized as 'advanced second generation taxoids'.
Synthesis and biological evaluation of amide-linked A-norpaclitaxels
Chordia, Mahendra D.,Kingston, David G. I.
, p. 5699 - 5710 (2007/10/03)
A novel amide-linked A-norpaclitaxel 3a and two 2-aroyl analogs 3b and 3c were prepared from 10-deacetyl baccatin III. Key steps in the synthesis were the conversion of 7-(triethylsilyl)baccatin m to its 13β-chloro-A-nor derivative 6, reaction with sodium
