TY - JOUR
T1 - Design, synthesis, and biological evaluation of new-generation taxoids
AU - Ojima, Iwao
AU - Chen, Jin
AU - Sun, Liang
AU - Borella, Christopher P.
AU - Wang, Tao
AU - Miller, Michael L.
AU - Lin, Songnian
AU - Geng, Xudong
AU - Kuznetsova, Larisa
AU - Qu, Chuanxing
AU - Gallager, David
AU - Zhao, Xianrui
AU - Zanardi, Ilaria
AU - Xia, Shujun
AU - Horwitz, Susan B.
AU - Mallen-St. Clair, Jon
AU - Guerriero, Jennifer L.
AU - Bar-Sagi, Dafna
AU - Veith, Jean M.
AU - Pera, Paula
AU - Bernacki, Ralph J.
PY - 2008/6/12
Y1 - 2008/6/12
N2 - 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-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed "third- generation taxoids". 19 (SB-T-1214), 14i (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in β-tubulin as well, wherein the drug resistance is mediated by the β-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.
AB - 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-resistant cell lines, and several taxoids exhibited virtually no difference in potency against the drug-sensitive and drug-resistant cell lines. These exceptionally potent taxoids were termed "third- generation taxoids". 19 (SB-T-1214), 14i (SB-T-121303), and 14i (SB-T-1213031) exhibited excellent activity against paclitaxel-resistant ovarian cancer cell lines with mutations in β-tubulin as well, wherein the drug resistance is mediated by the β-tubulin mutation. These taxoids were found to possess exceptional activity in promoting tubulin assembly, forming numerous very short microtubules similar to those formed by discodermolide. Taxoids 19 and 14g also showed excellent cytotoxicity against four pancreatic cancer cell lines, expressing three to four multidrug-resistant genes. Moreover, taxoid 19 exhibited excellent in vivo efficacy against highly drug-resistant CFPAC-1 pancreatic as well as DLD-1 human colon tumor xenografts in mice.
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U2 - 10.1021/jm800086e
DO - 10.1021/jm800086e
M3 - Article
C2 - 18465846
AN - SCOPUS:44949142967
SN - 0022-2623
VL - 51
SP - 3203
EP - 3221
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
ER -
