178250-07-2Relevant academic research and scientific papers
Fluorinated taxane compound, preparation method therefor and application of fluorinated taxane compound
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, (2019/08/30)
The invention discloses a fluorinated taxane compound, a preparation method therefor and an application of the fluorinated taxane compound. The compound has a structural general formula represented bya formula I. Proven by pharmacological experiments, compared with paclitaxel, a series of fluorinated taxane derivatives synthesized by the method have cytotoxicity superior to that of the paclitaxelto a multidrug-resistant human mammary cancer cell line MCF-7/Adr and an ovarian cancer cell line NCI/Adr and represent cytotoxicity superior to that of the paclitaxel to a colon cancer cell line HCT-116 with overexpressed neoplasm stem cells.
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),
FLUOROTAXOIDS
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Page/Page column 15, (2008/06/13)
The invention relates to fluorinated second generation taxoid compounds, pharmaceutical formulations thereof, and their use for inhibiting the growth of cancer cells in a mammal.
Trifluoromethyl- and difluoromethyl-β-lactams as useful building blocks for the synthesis of fluorinated amino acids, dipeptides, and fluoro-taxoids
Kuznetsova, Larisa,Ungureanu, Ioana Maria,Pepe, Antonella,Zanardi, Ilaria,Wu, Xinyuan,Ojima, Iwao
, p. 487 - 500 (2007/10/03)
Enantiopure 1-acyl-3-hydroxyl-4-CF2H-azetidin-2-ones and 1-acyl-3-hydroxy-4-CF3-azetidin-2-ones serve as versatile intermediates for the syntheses of CF2- and CF3-containing α-hydroxy-β-amino acids, dipeptides,
Structure-activity relationship study of taxoids for their ability to activate murine macrophages as well as inhibit the growth of macrophage-like cells
Ojima, Iwao,Fumero-Oderda, Cecilia L.,Kuduk, Scott D.,Ma, Zhuping,Kirikae, Fumiko,Kirikae, Teruo
, p. 2867 - 2888 (2007/10/03)
A series of new taxoids modified at the C-3′, C-3′N, C-10, C-2 and C-7 positions has been designed, synthesized and evaluated for their potency to induce NO and TNF production by peritoneal murine macrophages (Mφ) from LPS-responsive C3H/HeN and LPS-hyporesponsive C3H/HeJ strains and human blood cells, and for their ability to inhibit the growth of Mφ-like cell lines J774.1 and J7.DEF3. The SAR-study has shown that the nature of the substituents at these positions have critical effect on the induction of TNF and NO production by Mφ. Positions C-3′ and C-10 are the most flexible and an intriguing effect of the length of the substituents at the C-10 position is observed for taxoids bearing a straight chain alkanoyl moiety. An aromatic group at the C-3′N and C-2 positions is required for the activity, while only hydroxyl or acetyl substituents seem to be tolerated at the C-7 position. The natural stereochemistry in the C-13 isoserine side chain of the taxoids is an absolute requirement for macrophage activation. It has also been clearly shown that there is no correlation between the ability of the taxoids to induce TNF/NO production in C3H/HeN Mφ and the cytotoxicity against Mφ-like cells.
Syntheses and structure-activity relationships of taxoids derived from 14β-hydroxy-10-deacetylbaccatin III
Ojima, Iwao,Slater, John C.,Kuduk, Scott D.,Takeuchi, Craig S.,Gimi, Rayomand H.,Sun, Chung-Ming,Park, Young Hoon,Pera, Paula,Veith, Jean M.,Bernacki, Ralph J.
, p. 267 - 278 (2007/10/03)
A series of new taxoids derived from 14β-hydroxy-10-deacetylbaccatin III was synthesized by means of the β-lactam synthon method. Most of the new taxoids thus synthesized possess excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A5
