Synthesis and biological evaluation of new paclitaxel analogs and discovery of potent antitumor agents

Abstract

Reaction of 10-deacetylbaccatin III (III) and its 7-TES derivative (IV) with DAST under various conditions resulted in the formation of an array of new fluorinated and non-fluorinated 13-keto taxoid compounds (2a–4a) through a vinylogous pinacol-pinacolone rearrangement. Further fluorination of some of these products (2a, 3a) with NFSi or Selectfluor gave additional derivatives. Sodium borohydride reduction of the 13-keto group of these products (2a, 2b, 3a, 3b, 4a, 8, 9, 11–14) led to a series of 9α-hydroxy taxoid derivatives, which were esterified using the docetaxel side chain employing the corresponding protected β-lactam, followed by deprotection to furnish a library of docetaxol analogs and related compounds. A selected number of synthesized compounds (7, 10, 19a, 19b, 21a, 21b, 23, 27, 29, 34–36) were submitted to the National Cancer Institute (NCI) 60 cell line screening program and tested for cytotoxic properties. Taxoids 19a, 19b, 21a, 21b, 23, 27, 29, 34 and 35 were found to exhibit significant anticancer activity against various cancerous cell lines with 23, 27, and 29 being the most potent compounds, demonstrating GI50 values of ≤ 5 nM in several assays.

Folate-decorated redox/pH dual-responsive degradable prodrug micelles for tumor triggered targeted drug delivery

“…1 Although they are relatively potent and clinically active, the side effects associated with PTX including nausea, vomiting, diarrhea, mucositis, myelosuppression, cardiotoxicity, has 10 presented a serious concern in clinic. 2,3 Also, the clinical use of PTX is limited by its poor water solubility (~ 0.3 µg/mL) and pharmacokinetic characteristics, high systemic exposure and the lack of selective tumor uptake, which decreases the intracellular drug accumulation and reduces the efficacy of cancer 15 chemotherapy.…”

Anticancer Drugs Targeting Tubulin and Microtubules

“…Generated from Protein Data Bank entry 1JFF and displayed with Chimera 1.8.1. The large number of taxol analogs that have been synthesized has allowed the establishment of several SARs, 57 which are summarized as follows: 68 1. The hydroxyl group 1 is not essential and can be removed, epimerized, or esterified.…”

“…69 This binding model has been confirmed by the synthesis of a macrocyclic analog that adopts the T-Taxol conformation and is significantly more active than paclitaxel in both cytotoxicity and tubulin polymerization assays; 70 it is being used in the design of new taxanes. 71 The clinical success of taxanes, many of which are under clinical development, 72 continues to promote new synthetic efforts 73 and has prompted an intensive search for drugs with a related mechanism of action. This search has led to the identification of several families of natural products that bind to the taxane site and share the ability of taxol to promote microtubule assembly and induce mitotic arrest.…”

Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities

“…12 Nicolaou and Valiulin explored reactions of 10-deacetylbaccatin III with diethylaminosulfur trifluoride (DAST) under various conditions which yielded multiple new fluorinated and non-fluorinated C13-keto taxoid analogues. 13 Further reductions of the C13-keto group resulted in a series of 13α-hydroxy taxoid derivatives. The esterification of 13α-hydroxy group with the docetaxel side chain was used to produce an array of docetaxel analogues and other related compounds.…”

“…13 Three of the docetaxel analogues were highly active in the NCI-60 cancer cell panel with broad efficacy and potencies with GI 50 values less than 5 nM. 13 …”