Pd-Catalyzed Asymmetric Allylic Etherification Using Chiral Biphenol-Based Diphosphinite Ligands and Its Application for The Formal Total Synthesis of (−)-Galanthamine

A library of novel chiral biphenol-based diphosphinite (BOP) ligands was designed and created. These BOP ligands were applied to a Pd-catalyzed intermolecular allylic etherification reaction, which provided a key intermediate for the formal total synthesis of (−)-galanthamine with 97% ee in 97% yield

Design, Synthesis, and Biological Evaluation of Theranostic Vitamin–Linker–Taxoid Conjugates

Novel tumor-targeting theranostic conjugates <b>1</b> and <b>2</b>, bearing either a fluorine-labeled prosthetic as a potential ¹⁸F-PET radiotracer (<b>1</b>) or a fluorescence probe (<b>2</b>) for internalization studies in vitro, were designed and synthesized. We confirmed efficient internalization of <b>2</b> in biotin-receptor positive (BR+) cancer cells via receptor-mediated endocytosis (RME) based on flow cytometry and confocal fluorescence microscopy (CFM) analyses, which exhibited very high specificity to BR+ cancer cells. The potency and cancer-cell selectivity of <b>1</b> were evaluated against MX-1, L1210FR and ID8 cancer cells (BR+) as well as L1210 cells and WI38 normal human lung fibroblast cells (biotin-receptor negative: BR−). In particular, we designed and performed an assay in the presence of glutathione ethyl ester (GSH-OEt) wherein only <b>1</b> molecules internalized into cells via RME in the first 24 h period exert cytotoxic effect. The observed selectivity of <b>1</b> was remarkable, with 2 orders of magnitude difference in IC₅₀ values between BR+ cancer cells and WI38 cells, demonstrating a salient feature of this tumor-targeted drug delivery system

Synthesis of a Next-Generation Taxoid by Rapid Methylation Amenable for ¹¹C‑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 ¹¹C, a commonly employed positron-emitting radionucleide, via methyl iodide at the last step of chemical synthesis. This synthetic route features a highly stereoselective chiral ester enolate–imine cyclocondensation, regioselective hydrostannation of the resulting β-lactam, and the Stille coupling of the novel vinylstannyl taxoid intermediate with methyl iodide. Conditions have been established to allow the rapid methylation and HPLC purification of the target compound in a time frame amenable to ¹¹C-labeling for applications to PET studies

Design, Synthesis, and Biological Evaluations of Asymmetric Bow-Tie PAMAM Dendrimer-Based Conjugates for Tumor-Targeted Drug Delivery

A unique asymmetric bow-tie poly­(amidoamine) (PAMAM) dendrimer (ABTD) scaffold was designed and developed as a well-defined macromolecular carrier for tumor-targeted drug delivery. The ABTD scaffold in this study consists of a G3-half-dendron (G3-HD) unit and a G1-half-dendron (G1-HD) unit, bearing thiol moiety in each unit and a bis­(maleimide) linker unit, which undergo sequential thiol–maleimide coupling to assemble the scaffold. This assembly methodology is applicable to all other combinations of different generations of PAMAM dendrimers. In the prototype ABTD in this study, 16 biotin moieties were tethered to the G3-HD unit and 4 payloads (new-generation taxoid) to the G1-HD via a self-immolative linker to form an ABTD-tumor-targeting conjugate (ABTD-TTC-1). Two other ABTD-TTCs were synthesized, wherein the G1-HD unit was tethered to a fluorescence-labeled taxoid or to a fluorescent probe. These three ABTD-TTCs were constructed by using a common key ABTD <b>6</b> bearing a terminal acetylene group in the G1-HD unit, which was fully characterized as a single molecule by high-resolution mass spectrometry and NMR despite its high molecular weight (<i>M</i>_w: 12 876). Then, the click reaction was employed to couple ABTD <b>6</b> with a small-molecule payload or fluorescence probe unit bearing a terminal azide moiety. ABTD-TTC-3, as a surrogate of ABTD-TTC-2, showed substantially enhanced internalization into two cancer cell lines via receptor-mediated endocytosis, attributed to multibinding effect. ABTD-TTC-1 exhibited a remarkable selectivity to cancer cells (1400–7500 times) compared to human normal cells, which demonstrates the salient feature and bright prospect of the ABTD-based tumor-targeted drug-delivery system

SB-RA-2001 Inhibits Bacterial Proliferation by Targeting FtsZ Assembly

FtsZ has been recognized as a promising antimicrobial drug target because of its vital role in bacterial cell division. In this work, we found that a taxane SB-RA-2001 inhibited the proliferation of <i>Bacillus subtilis</i> 168 and <i>Mycobacterium smegmatis</i> cells with minimal inhibitory concentrations of 38 and 60 μM, respectively. Cell lengths of these microorganisms increased remarkably in the presence of SB-RA-2001, indicating that it inhibits bacterial cytokinesis. SB-RA-2001 perturbed the formation of the FtsZ ring in <i>B. subtilis</i> 168 cells and also affected the localization of the late cell division protein, DivIVA, at the midcell position. Flow cytometric analysis of the SB-RA-2001-treated cells indicated that the compound did not affect the duplication of DNA in <i>B. subtilis</i> 168 cells. Further, SB-RA-2001 treatment did not affect the localization of the chromosomal partitioning protein, Spo0J, along the two ends of the nucleoids and also had no discernible effect on the nucleoid segregation in <i>B. subtilis</i> 168 cells. The agent also did not appear to perturb the membrane potential of <i>B. subtilis</i> 168 cells. <i>In vitro</i>, SB-RA-2001 bound to FtsZ with modest affinity, promoted the assembly and bundling of FtsZ protofilaments, and reduced the GTPase activity of FtsZ. GTP did not inhibit the binding of SB-RA-2001 to FtsZ, suggesting that it does not bind to the GTP binding site on FtsZ. A computational analysis indicated that SB-RA-2001 binds to FtsZ in the cleft region between the C-terminal domain and helix H7, and the binding site of SB-RA-2001 on FtsZ resembled that of PC190723, a well-characterized inhibitor of FtsZ. The findings collectively suggested that SB-RA-2001 inhibits bacterial proliferation by targeting the assembly dynamics of FtsZ, and this can be exploited further to develop potent FtsZ-targeted antimicrobials

Design, Synthesis, and Biological Evaluations of Tumor-Targeting Dual-Warhead Conjugates for a Taxoid–Camptothecin Combination Chemotherapy

Novel tumor-targeting dual-warhead conjugates, <b>2</b> (DW-1) and <b>3</b> (DW-2), which consist of a next-generation taxoid, <b>1</b> (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 <b>2</b> 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, <b>2</b> exhibited IC₅₀ values of 3.22–9.80 nM against all BR+ cancer cell lines, and 705 nM against WI38. Thus, there was a two orders of magnitude higher selectivity to cancer cells. Also, a clear cooperative effect was observed for the taxoid–camptothecin combination when two drugs were delivered to the cancer cells specifically in the form of a dual-warhead conjugate

Cell cycle profile in response to docetaxel treatment.

(A) DU145, (B) DU145 KD, (C) DU145-TXR, and (D) DU145-TXR KD cells were treated with vehicle (0.1% DMSO), 3 nM, or 30 nM docetaxel for 72 h and subsequently stained with PI and analyzed by flow cytometry. *, p < 0.05; ***, p < 0.001 (n = 3).</p

Fatty Acid Binding Protein 5 Regulates Docetaxel Sensitivity in Taxane-Resistant Prostate Cancer Cells

   Prostate cancer is a leading cause of cancer-related deaths in men in the United States. Although treatable when detected early, prostate cancer commonly transitions to an aggressive castration-resistant metastatic state. While taxane chemotherapeutics such as docetaxel are mainstay treatment options for prostate cancer, taxane resistance often develops. Fatty acid binding protein 5 (FABP5) is an intracellular lipid chaperone that is upregulated in advanced prostate cancer and is implicated as a key driver of its progression. The recent demonstration that FABP5 inhibitors produce synergistic inhibition of tumor growth when combined with taxane chemotherapeutics highlights the possibility that FABP5 may regulate other features of taxane function, including resistance. Employing taxane-resistant DU145-TXR cells and a combination of cytotoxicity, apoptosis, and cell cycle assays, our findings demonstrate that FABP5 knockdown sensitizes the cells to docetaxel. In contrast, docetaxel potency was unaffected by FABP5 knockdown in taxane-sensitive DU145 cells. Taxane-resistance in DU145-TXR cells stems from upregulation of the P-glycoprotein ATP binding cassette subfamily B member 1 (ABCB1). Expression analyses and functional assays confirmed that FABP5 knockdown in DU145-TXR cells markedly reduced ABCB1 expression and activity, respectively. Our study demonstrates a potential new function for FABP5 in regulating taxane sensitivity and the expression of a major P-glycoprotein efflux pump in prostate cancer cells.  </p

FABP5 expression and docetaxel sensitivity of DU145 and DU145 TXR cells.

(A) qPCR and (B) western blotting demonstrates FABP5 expression in DU145 and DU145-TXR cells and confirms successful FABP5 KD in the corresponding cell-lines (n = 3). (C) Quantification of western blots presented as FABP5 / β-Actin (n = 3). (D) Cytotoxicity of docetaxel in taxane-resistant DU145-TXR and taxane-sensitive DU145 cells and in cells bearing an FABP5 KD. The IC50 values for docetaxel cytotoxicity were 6.1 nM, 5.3 nM, >100 nM, and 4.4 nM in DU145, DU145 KD, DU145-TXR, and DU145-TXR KD cells, respectively. **, p < 0.01; ***, p < 0.001 (n = 4). Data are reported as % viability of the respective vehicle controls.</p

Percent viable and apoptotic cells for DU145, DU145-TXR after DTX time course treatment.

Percent viable and apoptotic cells for DU145, DU145-TXR after DTX time course treatment.</p