Synthesis and Biological Evaluation of 2-Acyl Analogues of Paclitaxel (Taxol)

Kingston, David G. I.; Chaudhary, Ashok; Chordia, Mahendra D.; Gharpure, Milind M.; Gunatilaka, A. A. Leslie; Higgs, P. I.; Rimoldi, John M.; Samala, Lakshman; Jagtap, Prakash G.; Giannakakou, Paraskevi; Jiang, Yi; Lin, Chih‐Min; Hamel, Ernest; Long, Byron H.; Fairchild, Craig R.; Johnston, Kathy

doi:10.1021/jm980229d

Cited by 67 publications

(59 citation statements)

References 35 publications

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“…Unlike some other chemotypes that interfere with tubulin assembly, including a series of C-2-substituted paclitaxel analogs (Kingston et al, 1998), there is poor correlation thus far between assembly effects and cellular effects of laulimalide site compounds. This seems to be the case whether the net effect on assembly is measured, as shown here (Fig.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effects of Peloruside A and Laulimalide with Taxoid Site Drugs, but Not with Each Other, on Tubulin Assembly

Hamel¹,

Day²,

Miller³

et al. 2006

Mol Pharmacol

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124

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Previous studies on the drug content of pelleted tubulin polymers suggest that peloruside A binds in the laulimalide site, which is distinct from the taxoid site. In a tubulin assembly system containing microtubule-associated proteins and GTP, however, peloruside A was significantly less active than laulimalide, inducing assembly in a manner that was most similar to sarcodictyins A and B. Because peloruside A thus far seems to be the only compound that mimics the action of laulimalide, we examined combinations of microtubule-stabilizing agents for synergistic effects on tubulin assembly. We found that peloruside A and laulimalide showed no synergism but that both compounds could act synergistically with a number of taxoid site agents [paclitaxel, epothilones A/B, discodermolide, dictyostatin, eleutherobin, the steroid derivative 17␤-acetoxy-2-ethoxy-6-oxo-B-homo-estra-1,3,5(10)-trien-3-ol, and cyclostreptin]. None of the taxoid site compounds showed any synergism with each other. From an initial study with peloruside A and cyclostreptin, we conclude that the synergism phenomenon derives, at least in part, from an apparent lowering of the tubulin critical concentration with drug combinations compared with single drugs. The apparent binding of peloruside A in the laulimalide site led us to attempt construction of a pharmacophore model based on superposition of an energy-minimized structure of peloruside A on the crystal structure of laulimalide. Although the different sizes of the macrocycles limited our ability to superimpose the two molecules, atom correspondences that were observed were consistent with the difficulty so far experienced in creation of fully active analogs of laulimalide.

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Section: Discussionmentioning

confidence: 99%

Synergistic Effects of Peloruside A and Laulimalide with Taxoid Site Drugs, but Not with Each Other, on Tubulin Assembly

Hamel¹,

Day²,

Miller³

et al. 2006

Mol Pharmacol

Self Cite

124

114

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“…The crude product was purified by column chromatography on silica gel (hexanes/EtOAc = 1/1) to afford 81.1, 84.4, 120.7, 127.3, 128.5, 129.1, 130.8, 132.8, 134.4, 138.3, 142.6, 155.4 Other taxoids 14b-p, 15c-e and 15g were prepared in the same manner and characterization data are shown below. -2-(3-methoxybenzoyl)-10-acetyl-3'-dephenyl-3'-(2-methylprop-l-enyl) 16 Na + : 880.3766, obtained: 880.3732 (Δ = −3.9 ppm). HPLC analysis using a Phenomenex Curosil-B column (CH 3 CN/water (2/3) as the solvent system with a flow rate of 1 mL/min; UV 230 nm and 254 nm) showed ≥95% purity.…”

Section: Synthesis Of Second-and Third-generation Taxoids 14 Through mentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of New-Generation Taxoids

et al. 2008

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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 potentency against multidrug drug-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), 14g (SB-T-121303), and 14i (SB-T-1213031), exhibited excellent activity against paclitaxelresistant ovarian cancer cell lines as well, wherein the drug-resistance is mediated by 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 4 pancreatic cancer cell lines, expressing 3-4 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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“…12,21,22 The radiochemical esterification of 4 with 2, involving a large excess of precursor (2) compared to 4, however, was unsuccessful after numerous efforts, although success of this type of reaction has been shown under standard (organic) conditions. 13,14,17 Analysis of the reaction mixtures indicated that the anion of 2 was not properly formed -recovery of unreacted 2 NLi lead to the decomposition of 4 (no conversion to the acid, however). The amounts of the moisture-sensitive bases used were very small (ml range) and although every attempt was made to exclude moisture from the system (vials, tubing, syringes, chemicals and solvents), it was unclear how much base remained intact during handling.…”

Section: Resultsmentioning

confidence: 99%

“…The tert-butyl carbamate moiety of docetaxel (side chain) was anticipated to be unstable under acidic hydrolysis and deprotection reaction conditions, so a fast and quantitative removal of the protection groups under basic conditions was a necessity. Using published methods, 14,16,18,19 the 2 0 -hydroxyl was protected with a tert-butyldimethylsilyl protecting group and both the 7-and 10-hydroxyls with triethylsilyl protecting groups in an average overall yield of 86 AE 4%. The bulkiness of the former protecting group was shown to be essential for the prevention of cleavage of the entire C-13 side chain.…”

Section: Introductionmentioning

confidence: 99%