Syntheses and Structure−Activity Relationships of Taxoids Derived from 14β-Hydroxy-10-deacetylbaccatin III

Abstract

A series of new taxoids derived from 14 beta-hydroxy-10-deacetylbaccatin III was synthesized by means of the beta-lactam synthon method. Most of the new taxoids thus synthesized possess excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines, and several of these taxoids show subnanomolar IC50 values which are severalfold to 1 order of magnitude better than those of paclitaxel and docetaxel. Modifications at the 3'- and 3'-N-positions exert marked effects on the activity. For the substituents at C-3', the cytotoxicity decreases in the order 2-furyl approximately 2-methyl-1-propenyl > or = 2-methylpropyl > (E)-1-propenyl > or = n-propyl > phenyl > > 2,2-dimethylpropyl. For the 3'-N substituents, the activity decreases in the order t-BuOCO > Ph > n-hexanoyl. A significant increase in the cytotoxicity against the doxorubicin-resistant human breast cancer cell line MCF7-R that expresses the multidrug resistance (MDR) phenotype is observed by the proper modification of the substituent at C-10. The observed remarkable effects of the substituents at C-10 on the activity against MCF7-R can be ascribed to the effective inhibition of the binding of these new taxoids to P-glycoprotein that is responsible for MDR.

A common pharmacophore for cytotoxic natural products that stabilize microtubules

“…Deprotection of the TES groups with HF͞pyridine, followed by reprotection at the 7-position with TES and acetylation at the 10-position, gave baccatin 8 in 56% yield over three steps. Coupling of baccatin 9 with ␤-lactam 10, obtained in good yields and high enantiomeric excess by the previously published procedure (6,19), provided coupling product 11 in 64% yield. The ring-closing metathesis of 11 with Ru-benzylidene complex in CH 2 Cl 2 (1 mM) proceeded smoothly to afford the protected 18-membered macrocycle as the pure E isomer, which afforded hybrid construct 6 on deprotection with HF͞ † † While we used two different force fields-i.e., Tripos (SYBYL 6.4) and CVFF (DISCOVER 95.0)-all energy optimizations were performed with the Tripos force field.…”

“…1) is a powerful resource in cancer chemotherapy (1)(2)(3)(4)(5)(6)(7). It was approved by the Food and Drug Administration in the United States for the treatment of advanced ovarian cancer (1992) and metastatic breast cancer (1994).…”

“…It was approved by the Food and Drug Administration in the United States for the treatment of advanced ovarian cancer (1992) and metastatic breast cancer (1994). Clinical studies on the treatment of other cancers with paclitaxel and closely related synthetic analogues, as well as combination protocols, are being pursued (1)(2)(3)(4)(5)(6)(7).…”

Second-generation taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes

“…Second-generation taxanes SB-T-12851, SB-T-12852, SB-T-12853, SB-T-12854 [20,37], SB-T-1214 [16,36], IDN5109 [20,21], and IDN5390 [22] were synthesized by the Ojima laboratory, State University of New York at Stony Brook, U. S. A. Their structures are shown in Fig.…”

Synthesis of a 11C‐labelled taxane derivative by [1‐11C]acetylation

“…3 This report describes the 11 C-labelling of the taxane derivative BAY 59-8862 (1) using [1-11 C]acetyl chloride. Compound 1, 5b, 20-epoxy-1,2a,4,7b,13a, 14b-heptahydroxytax-11-en-9-one-1,14-carbonate-4,10-diacetate-2-benzoate 13-[(2R,3S)-3-(N-tert-butoxycarbonyl)-amino-2-hydroxy-5-methylhexanoate] (see Scheme 1) was shown to be a new potent anticancer drug 4 which is intended for the therapy of brain metastases of breast cancer.…”