Synthesis of a Next-Generation Taxoid by Rapid Methylation Amenable for C-Labeling.

Next-generation taxoids, such as SB-T-1214, are highly potent cytotoxic agents that exhibit remarkable efficacy against drug-resistant tumors in vivo, including those that overexpress the P-glycoprotein (Pgp) efflux pump. As SB-T-1214 is not a substrate for Pgp-mediated efflux, it may exhibit a markedly different biodistribution and tumor-accumulation profile than paclitaxel or docetaxel, which are both Pgp substrates. To investigate the biodistribution and tumor-accumulation levels of SB-T-1214 using positron emission tomography (PET), a new synthetic route has been developed to allow the incorporation of C, a commonly employed positron-emitting radionucleide, via methyl iodide at the last step of chemical synthesis.

Differing Mechanisms of Death Induction by Fluorinated Taxane SB-T-12854 in Breast Cancer Cells.

Background/aim: Classical taxanes are routinely used in cancer therapy. In this study, mechanisms involved in death induction by the novel fluorine-containing taxane SB-T-12854 were investigated.

Materials And Methods: We employed breast cancer SK-BR-3, MCF-7 and T47D cell lines to assess activation of individual caspases, changes in the expression of proteins of the Bcl-2 family, and the release of pro-apoptotic factors from mitochondria into the cytosol after SB-T-12854 treatment.

Design, synthesis and biological evaluation of a highly-potent and cancer cell selective folate-taxoid conjugate.

The folate receptor (FR) has been widely recognized as an excellent target for the tumor-selective delivery of cytotoxic agents, and four folate-drug conjugates have entered clinical evaluations for the treatment of solid tumors to date. However, most of these conjugates required structural modification of the cytotoxic warheads in order to achieve efficient drug release from the linkers. We designed and constructed a novel folate conjugate of a highly-potent next-generation taxoid, SB-T-1214, by exploiting bioorthogonal Cu-free 'click' chemistry.

Poly(2-oxazoline) based micelles with high capacity for 3rd generation taxoids: preparation, in vitro and in vivo evaluation.

The clinically and commercially successful taxanes, paclitaxel and docetaxel suffer from two major drawbacks, namely their very low aqueous solubility and the risk of developing resistance. Here, we present a method that overcomes both drawbacks in a very simple manner. We formulated 3rd generation taxoids, able to avoid common drug resistance mechanisms with doubly amphiphilic poly(2-oxazoline)s (POx), a safe and highly efficient polymer for the formulation of extremely hydrophobic drugs.

Design, Synthesis and Application of Fluorine-Labeled Taxoids as F NMR Probes for the Metabolic Stability Assessment of Tumor-Targeted Drug Delivery Systems.

Novel tumor-targeting drug conjugates, BLT-F () and BLT-S-F (), bearing a fluorotaxoid as the warhead, a mechanism-based self-immolative disulfide linker, and biotin as the tumor-targeting module, were designed and synthesized as F NMR probes. Fluorine atoms and CF groups were strategically incorporated into the conjugates to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time monitoring with F NMR. Time-resolved F NMR study on probe disclosed a stepwise mechanism for release of a fluorotaxoid, which might not have been detected by other analytical methods.

Design, synthesis, and biological evaluations of tumor-targeting dual-warhead conjugates for a taxoid-camptothecin combination chemotherapy.

Novel tumor-targeting dual-warhead conjugates, 2 (DW-1) and 3 (DW-2), which consist of a next-generation taxoid, 1 (SB-T-1214), and camptothecin as two warheads, self-immolative disulfide linkers for drug release, biotin as the tumor-targeting moiety, and 1,3,5-triazine as the tripod splitter module, were designed and synthesized. The potency of 2 was evaluated against MX-1, MCF-7, ID8, L1210FR (BR+, biotin receptor overexpressed) and WI38 (BR-, normal) cell lines in the absence and presence of glutathione (GSH), which is an endogenous thiol that triggers drug release inside the cancer cells. With the GSH and resuspension protocol, 2 exhibited IC50 values of 3.

Fluorine-Containing Taxoid Anticancer Agents and Their Tumor-Targeted Drug Delivery.

A long-standing problem of conventional chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects.

Synthesis and Biological Evaluation of Novel 3'-Difluorovinyl Taxoids.

A series of 3'-difluorovinyl taxoids with C10 modifications, as well as those with C2 and C10 modifications, were strategically designed to block the metabolism by cytochrome P-450 3A4 enzyme and synthesized. These novel difluorovinyl taxoids were evaluated for their cytotoxicity against drug-sensitive human breast (MCF7), multidrug-resistant (MDR) human ovarian (NCI/ADR), human colon (HT-29) and human pancreatic (PANC-1) cancer cell lines. 3'-Difluorovinyl taxoids exhibit several to 16 times better activity against MCF7, HT-29 and PANC-1 cell lines and up to three orders of magnitude higher potency against NCI/ADR cell line as compared to paclitaxel.

Tumor-targeting drug delivery of new-generation taxoids.

A long-standing problem of conventional cancer chemotherapy is the lack of tumor specificity. Tumor-targeting drug-delivery systems have been explored to overcome this problem. These systems combine a powerful cytotoxic anticancer agent with a tumor-targeting molecule via a 'smart' linker to form highly efficacious drug conjugates.