New skeletal rearrangements of C and D rings of a 13-oxobaccatin III derivative (original) (raw)
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Synthesis of Paclitaxel. 2. Construction of the ABCD Ring and Formal Synthesis
Organic Letters, 2015
A formal synthesis of the antitumor diterpenoid paclitaxel (Taxol) is described. The ABC ring of paclitaxel, synthesized starting from 1,3-cyclohexanedione and tri-Oacetyl-D-glucal by SmI 2-mediated cyclization as the key transformation, was successfully converted to Takahashi's tetracyclic oxetane intermediate. A double Chugaev reaction was employed for introduction of the strained bridgehead olefin, and stereoselective formation of the oxetane ring afforded the known synthetic intermediate, completing the formal synthesis of paclitaxel.
Synthesis and Biological Evaluation ofN-(Arylsulfanyl)carbonyl Analogues of Paclitaxel (Taxol
Chemistry & Biodiversity, 2006
Four new N-(arylsufanyl)carbonyl paclitaxel analogues (2a–d) were prepared from 7-(triethylsilyl)-protected baccatin III (5). Their cytotoxicities against human ovarian (A2780) and prostate cancer (PC3) cell lines, as well as their tubulin-assembly activities, were determined. In these assays, the new compounds showed rather weak activities, one two orders of magnitude below those of paclitaxel (taxol; 1). The known 3′-N-[(thiophen-2-yl)carbonyl] paclitaxel analogue 3 was also prepared. As previously reported, 3 exhibited strongly improved cytotoxicities and tubulin-assembly activities as compared to paclitaxel (1).
Structure−Activity Relationships of Ring C-Secotaxoids. 1. Acylative Modifications †
Journal of Natural Products, 2004
The acylative modification of IDN 5390 (3a), a 7,8-secotaxoid under preclinical development, was investigated. A modest decrease of potency was observed upon acylation of the primary and the enolic hydroxyls, suggesting that, just like in paclitaxel, the hydroxyl groups in the upper right-hand sector are not critical for cytotoxicity. The activity of these analogues, and especially of the chemically robust carbonates 3c and 3d, makes it unlikely that the activity of IDN 5390 is due to in vivo oxidation to a fledgling 7-aldehyde and re-aldolization to the corresponding taxane derivative.
Journal of Medicinal Chemistry, 1994
Synthesis and cytotoxicity of the new analogs (11-13) of docetaxel possessing cyclohexyl groups instead of phenyl groups at the C-3' and/or C-2 benzoate positions are described. The C-2 cyclohexanecarboxylate analog of paclitaxel(15) is also synthesized for comparison. The potency of these new taxoids were examined for their inhibitory activity for microtubule disassembly and also for their cytotoxicity against murine P388 leukemia cell line as well as doxorubicinresistant P388 leukemia cell line (P388Dox). It is found that 3'-dephenyl-3'-cyclohexyldocetaxel (11) (0.7227 and 2-(hexahydro)docetaxel (12) (0.8527 possess strong inhibitory activity for microtubule disassembly equivalent to docetaxel(O.727, which is more potent than paclitaxel (1.027. The results clearly indicate that phenyl or an aromatic group a t (2-3' or C-2 is not a requisite for strong binding to the microtubules. This finding has opened an avenue for development of new nonaromatic analogs of docetaxel and paclitaxel. 3'-DephenyL3'-cyclohexyl-2-(hexahydro)docetaxel (13) (22') turns out to be a substantially weaker inhibitor. The cytotoxicities of 11-13 against P388 are, however, in the same range that is 8-12 times weaker than docetaxel and 4-6 times weaker than paclitaxel, i.e., 13 shows equivalent cytotoxicity to that of 11 or 12 in spite of much lower microtubule disassembly inhibitory activity. The cytotoxicities of these new taxoids against the P388/Dox cell line are only 2-2.5 times lower than that of docetaxel. The potency of 2-(hexahydro)paclitaxel(lS) for these assays is much lower than the docetaxel counterpart 12. The significant loss of activity in vivo against B16 melanoma is observed for 11-13, i.e., 11 is only marginal (T/C = 38% at 20 mg/kg/day), and 12 and 13 are inactive (T/C = 76% and 79%, respectively). This could be ascribed to faster metabolism, faster excretion or other bioavailability problems. * Rhhe-Poulenc Rorer.
Synthesis of biologically active 2-benzoyl paclitaxel analogues
Bioorganic & Medicinal Chemistry Letters, 1995
... MM Gharpure, JM Rimoldi, DGI Kingston, YQ Jiang and E. Hamel. Tetrahedron Lett. 35 (1994), p. 6839. Abstract | PDF (339 K) | View Record in Scopus | Cited By in Scopus (25). (12). For the synthesis and biological activity of heteroaromatic 2-benzoyl paclitaxel analogues see: ...
Synthesis and Biological Evaluation of 2-Acyl Analogues of Paclitaxel (Taxol)
J. Med. …, 1998
The anticancer drug paclitaxel (Taxol) has been converted to a large number of 2-debenzoyl-2-aroyl derivatives by three different methods. The bioactivities of the resulting analogues were determined in both tubulin polymerization and cytotoxicity assays, and several analogues with enhanced activity as compared with paclitaxel were discovered. Correlation of cytotoxicity in three cell lines with tubulin polymerization activity showed reasonable agreement. Among the cell lines examined, the closest correlation with antitubulin activity was observed with a human ovarian carcinoma cell line.