Development of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and Beyond

The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis, and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4⁺ cell types from bone marrow to peripheral circulation. We have discovered a novel series of pyrimidine-based CXCR4 antagonists, a representative (i.e., <b>16</b>) of which was tolerated at a higher dose and showed better HSC-mobilizing ability at the maximal response dose relative to the approved drug <b>1</b> (AMD3100), and thus considered a potential drug candidate for PBSCT indication. Docking compound <b>16</b> into the X-ray crystal structure of CXCR4 receptor revealed that it adopted a spider-like conformation striding over both major and minor subpockets. This putative binding mode provides a new insight into CXCR4 receptor–ligand interactions for further structural modifications

Development of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and Beyond

The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis, and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4⁺ cell types from bone marrow to peripheral circulation. We have discovered a novel series of pyrimidine-based CXCR4 antagonists, a representative (i.e., <b>16</b>) of which was tolerated at a higher dose and showed better HSC-mobilizing ability at the maximal response dose relative to the approved drug <b>1</b> (AMD3100), and thus considered a potential drug candidate for PBSCT indication. Docking compound <b>16</b> into the X-ray crystal structure of CXCR4 receptor revealed that it adopted a spider-like conformation striding over both major and minor subpockets. This putative binding mode provides a new insight into CXCR4 receptor–ligand interactions for further structural modifications

Targeting Tumor Associated Phosphatidylserine with New Zinc Dipicolylamine-Based Drug Conjugates

A series of zinc­(II) dipicolylamine (ZnDPA)-based drug conjugates have been synthesized to probe the potential of phosphatidylserine (PS) as a new antigen for small molecule drug conjugate (SMDC) development. Using <i>in vitro</i> cytotoxicity and plasma stability studies, PS-binding assay, <i>in vivo</i> pharmacokinetic studies, and maximum tolerated dose profiles, we provided a roadmap and the key parameters required for the development of the ZnDPA based drug conjugate. In particular, conjugate <b>24</b> induced tumor regression in the COLO 205 xenograft model and exhibited a more potent antitumor effect with a 70% reduction of cytotoxic payload compared to that of the marketed irinotecan when dosed at the same regimen. In addition to the validation of PS as an effective pharmacodelivery target for SMDC, our work also provided the foundation that, if applicable, a variety of therapeutic agents could be conjugated in the same manner to treat other PS-associated diseases

Stem Cell Mobilizers Targeting Chemokine Receptor CXCR4: Renoprotective Application in Acute Kidney Injury

We have discovered a novel series of quinazoline-based CXCR4 antagonists. Of these, compound <b>19</b> mobilized CXCR4⁺ cell types, including hematopoietic stem cells and endothelial progenitor cells, more efficiently than the marketed <b>1</b> (AMD3100) with subcutaneous administration at the same dose (6 mg/kg) in mice. This series of compounds thus provides a set of valuable tools to study diseases mediated by the CXCR4/SDF-1 axis, including myocardial infarction, ischemic stroke, and cancer metastasis. More importantly, treatment with compound <b>19</b> significantly lowered levels of blood urea nitrogen and serum creatinine in rats with renal ischemia-reperfusion injury, providing evidence for its therapeutic potential in preventing ischemic acute kidney injury. CXCR4 antagonists such as <b>19</b> might also be useful to increase circulating levels of adult stem cells, thereby exerting beneficial effects on damaged and/or inflamed tissues in diseases that currently are not treated by standard approaches

Bromomethylthioindole Inspired Carbazole Hybrids as Promising Class of Anti-MRSA Agents

Series of <i>N</i>-substituted carbazole analogues bearing an indole ring were synthesized as anti-methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) agents from a molecular hybridization approach. The representative compound <b>19</b> showed an MIC = 1 μg/mL against a panel of MRSA clinical isolates as it possessed comparable <i>in vitro</i> activities to that of vancomycin. Moreover, compound <b>19</b> also exhibited MIC = 1 μg/mL activities against a recent identified Z172 MRSA strain (vancomycin-intermediate and daptomycin-nonsusceptible phenotype) and the vancomycin-resistant <i>Enterococcus faecalis</i> (VRE) strain. In a mouse model with lethal infection of MRSA (4N216), a 75% survival rate was observed after a single dose of compound <b>19</b> was intravenously administered at 20 mg/kg. In light of their equipotent activities against different MRSA isolates and VRE strain, the data underscore the importance of designed hybrid series for the development of new <i>N</i>-substituted carbazoles as potential anti-MRSA agents

Discovery of 1‑(2,4-Dichlorophenyl)‑<i>N</i>‑(piperidin-1-yl)-4-((pyrrolidine-1-sulfonamido)methyl)-5-(5-((4-(trifluoromethyl)phenyl)ethynyl)thiophene-2-yl)‑1<i>H</i>‑pyrazole-3-carboxamide as a Novel Peripherally Restricted Cannabinoid‑1 Receptor Antagonist with Significant Weight-Loss Efficacy in Diet-Induced Obese Mice

After extensive synthetic efforts, we found that many structurally diverse bioisosteres could be generated via derivatizing the C-4 alkyl chain on the pyrazole ring of compound <b>3</b> (B/P = 1/33) with different electronegative groups. Especially when a sulfonamide or sulfamide moiety was added, resulting compounds exhibited not only potent CB1R activity but also a desired tPSA value over 90 Ų, a threshold considered to possess a low probability to cross BBB, leading to the identification of compound <b>4</b> (B/P = 1/64) as a peripherally restricted CB1R antagonist. Apart from its significant weight-loss efficacy in DIO mice, compound <b>4</b> also displays 163 clean off-target profiles and is currently under development for treating obesity and the related metabolic syndrome

Function-Oriented Development of CXCR4 Antagonists as Selective Human Immunodeficiency Virus (HIV)‑1 Entry Inhibitors

Motivated by the pivotal role of CXCR4 as an HIV entry co-receptor, we herein report a de novo hit-to-lead effort on the identification of subnanomolar purine-based CXCR4 antagonists against HIV-1 infection. Compound <b>24</b>, with an EC₅₀ of 0.5 nM against HIV-1 entry into host cells and an IC₅₀ of 16.4 nM for inhibition of radioligand stromal-derived factor-1α (SDF-1α) binding to CXCR4, was also found to be highly selective against closely related chemokine receptors. We rationalized that compound <b>24</b> complementarily interacted with the critical CXCR4 residues that are essential for binding to HIV-1 gp120 V3 loop and subsequent viral entry. Compound <b>24</b> showed a 130-fold increase in anti-HIV activity compared to that of the marketed CXCR4 antagonist, AMD3100 (Plerixafor), whereas both compounds exhibited similar potency in mobilization of CXCR4⁺/CD34⁺ stem cells at a high dose. Our study offers insight into the design of anti-HIV therapeutics devoid of major interference with SDF-1α function

Function-Oriented Development of CXCR4 Antagonists as Selective Human Immunodeficiency Virus (HIV)‑1 Entry Inhibitors

Motivated by the pivotal role of CXCR4 as an HIV entry co-receptor, we herein report a de novo hit-to-lead effort on the identification of subnanomolar purine-based CXCR4 antagonists against HIV-1 infection. Compound <b>24</b>, with an EC₅₀ of 0.5 nM against HIV-1 entry into host cells and an IC₅₀ of 16.4 nM for inhibition of radioligand stromal-derived factor-1α (SDF-1α) binding to CXCR4, was also found to be highly selective against closely related chemokine receptors. We rationalized that compound <b>24</b> complementarily interacted with the critical CXCR4 residues that are essential for binding to HIV-1 gp120 V3 loop and subsequent viral entry. Compound <b>24</b> showed a 130-fold increase in anti-HIV activity compared to that of the marketed CXCR4 antagonist, AMD3100 (Plerixafor), whereas both compounds exhibited similar potency in mobilization of CXCR4⁺/CD34⁺ stem cells at a high dose. Our study offers insight into the design of anti-HIV therapeutics devoid of major interference with SDF-1α function