- Synthesis and biological evaluation of novel 3′-difluorovinyl taxoids
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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.
- 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
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p. 177 - 188
(2013/01/13)
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- Design, synthesis and biological evaluation of novel fluorinated docetaxel analogues
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A series of novel fluorinated docetaxel analogues have been synthesized and evaluated in vitro and in vivo. Incorporated one, two or three fluorine atom(s) either at both meta position on C-2 benzolate and 3′-N-tert-butyloxyl group or only at 3′-N-tert-butyloxyl group has resulted in potent analogues which have comparable or superior in vitro and in vivo cytotoxicity to docetaxel. Among them, compounds 14d and 14e have displayed more potent cytotoxicity than docetaxel both in human cancer cell line SK-OV-3 in vitro and in human non-small cell lung cancer A549 xenografts in vivo. Preliminary data show that compound 14a has reduced acute animal toxicity in mice compared with docetaxel.
- Lu, Hong-Fu,Sun, Xun,Xu, Liang,Lou, Li-Guang,Lin, Guo-Qiang
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scheme or table
p. 482 - 491
(2009/09/06)
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- Syntheses and structure-activity relationships of novel 3′-difluoromethyl and 3′-trifluoromethyl-taxoids
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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),
- Kuznetsova, Larissa V.,Pepe, Antonella,Ungureanu, Ioana M.,Pera, Paula,Bernacki, Ralph J.,Ojima, Iwao
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scheme or table
p. 817 - 828
(2009/04/06)
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- Design, synthesis, and biological evaluation of new-generation taxoids
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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
- 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.
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scheme or table
p. 3203 - 3221
(2009/05/11)
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- Rotational-echo double-resonance NMR distance measurements for the tubulin-bound paclitaxel conformation
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The important anticancer drug Taxol (paclitaxel, PTX) owes its unique activity to its ability to bind to tubulin in a stoichiometric ratio and promote its assembly into microtubules. The conformation of the microtubule-bound drug has been the focus of num
- Paik, Younkee,Yang, Chao,Metaferia, Belhu,Tang, Shoubin,Bane, Susan,Ravindra, Rudravajhala,Shanker, Natasha,Alcaraz, Ana A.,Johnson, Scott A.,Schaefer, Jacob,O'Connor, Robert D.,Cegelski, Lynette,Snyder, James P.,Kingston, David G. I.
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p. 361 - 370
(2008/02/09)
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- Design, synthesis and structure-activity relationships of novel taxane-based multidrug resistance reversal agents
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A series of novel taxane-based multidrug resistance (MDR) reversal agents (TRAs) has been designed and synthesized. Structure - activity relationship (SAR) study clearly indicates that modification of the C-7 position with hydrophobic arenecarbonylcinnamoyl groups brings about high potency against drug efflux mediated by P-glycoprotein (P-gp). Six TRAs exhibit ability to modulate a wide range of ATP-binding cassette (ABC) transporters, such as P-gp, multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), which may serve as novel broad-spectrum modulators of ABC transporters.
- Ojima, Iwao,Borella, Christopher P.,Wu, Xinyuan,Bounaud, Pierre-Yves,Oderda, Cecilia Fumero,Sturm, Matthew,Miller, Michael L.,Chakravarty, Subrata,Chen, Jin,Huang, Qing,Pera, Paula,Brooks, Tracy A.,Baer, Maria R.,Bernacki, Ralph J.
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p. 2218 - 2228
(2007/10/03)
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- Synthesis and biological evaluation of novel taxoids designed for targeted delivery to tumors
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The use of drug-antibody conjugates affords a method for the targeted delivery of anticancer drugs specifically to cancer cells. Monoclonal antibodies alone usually do not possess high therapeutic efficacy, however, they are capable of targeting tumor mar
- Baloglu, Erkan,Miller, Michael L.,Roller, Elizabeth E.,Cavanagh, Emily E.,Leece, Barbara A.,Goldmacher, Victor S.,Chari, Ravi V.J.
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p. 5885 - 5888
(2007/10/03)
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- Structure-activity relationship study of taxoids for their ability to activate murine macrophages as well as inhibit the growth of macrophage-like cells
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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.
- Ojima, Iwao,Fumero-Oderda, Cecilia L.,Kuduk, Scott D.,Ma, Zhuping,Kirikae, Fumiko,Kirikae, Teruo
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p. 2867 - 2888
(2007/10/03)
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- Macrocycle formation by ring-closing metathesis. Application to the syntheses of novel macrocyclic taxoids
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A series of novel macrocyclic taxoids 6 and 6′ bearing 16-, 17-, and 18-membered rings connecting the substituants at the C-2 and C-3′ positions were designed and synthesized. The syntheses of these macrocycles 6 and 6′ were accomplished using the highly
- Ojima, Iwao,Lin, Songnian,Inoue, Tadashi,Miller, Michael L.,Borella, Christopher P.,Geng, Xudong,Walsh, John J.
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p. 5343 - 5353
(2007/10/03)
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- Synthesis of paclitaxel (docetaxel) / 2-deacetoxytaxinine J dimers
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Starting from taxanes available in multigram amounts from widespread ornamental yews (10-deacetylbaccatin III (4) and 2'-deacetoxyaustrospicatine (5)), two dimeric taxoids (3a, 3b) with potential dual target specificity (β-tubulin and P-gp) were synthesised. Both compounds lacked significant cytotoxicity, though 3b retained a strong activity in the tubulin depolimerisation assay.
- Appendino, Giovanni,Belloro, Emanuela,Jakupovic, Sven,Danieli, Bruno,Jakupovic, Jasmin,Bombardelli, Ezio
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p. 6567 - 6576
(2007/10/03)
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- Synthesis and structure-activity relationships of new second-generation taxoids
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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'.
- Ojima, Iwao,Wang, Tao,Miller, Michael L.,Lin, Songnian,Borella, Christopher P.,Geng, Xudong,Pera, Paula,Bernacki, Ralph J.
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p. 3423 - 3428
(2007/10/03)
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- New taxanes as highly efficient reversal agents for multidrug resistance in cancer cells
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New non-cytotoxic taxanes synthesized from 10-deacetylbaccatin III and special hydrophobic acylating agents show remarkable MDR reversal activity (≤99.8%) against drug-resistant human breast cancer cells when co-administered with paclitaxel or doxorubicin. This activity is ascribed to the highly efficient blocking of P-glycoprotein efflux by these new taxanes.
- Ojima, Iwao,Bounaud, Pierre-Yves,Takeuchi, Craig,Pera, Paula,Bernacki, Ralph J.
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p. 189 - 194
(2007/10/03)
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- Synthesis and Biological Evaluation of D-Ring-Modified Taxanes:1 5(20)-Azadocetaxel Analogs
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Two 5(20)-aza analogs of docetaxel, N-20-benzyl-5(20)-azadocetaxel (5) and 5(20)-azadocetaxel (6), have been synthesized from 10-deacetylbaccatin III. The key steps of this synthesis involved the direct introduction of a C-5 leaving group while ring opening and the intramolecular nucleophilic attack of the C-20 amino group at C-5. Both compounds were inactive on the in vitro cytotoxic assay, and only the azadocetaxel 6 retains an antitubulin activity, but 16 times less than docetaxel.
- Marder-Karsenti, Raphaele,Dubois, Joelle,Bricard, Laurent,Guenard, Daniel,Gueritte-Voegelein, Francoise
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p. 6631 - 6637
(2007/10/03)
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