For selected compounds, we are devising synthetic methods to probe structure–activity relationships (SAR) and to obtain larger quantities of material for biological evaluation, including toxicity, pharmacokinetic and efficacy studies in animal models, which we will carry out in due course. Molecules of particular interest include largazoles and apratoxins, which we discovered and characterized in our lab.
Largazole, which we isolated from a Floridian cyanobacterium, is the most potent natural HDAC inhibitor to date. We described a concise and convergent synthesis (8 steps, 19% overall yield), which allowed its extension to the preparation of a series of analogues. SAR studies revealed that the thiol group is the pharmacophore of the natural product and liberated during protein-assisted thioester hydrolysis to largazole thiol. We determined that largazole inhibits HDACs in vivo, consequently modulates gene expression and thereby shows efficacy in solid tumor xenograft mouse models and bone-forming efficacy in mouse and rabbit models. The dual action of largazole to stimulate bone formation and inhibit bone resorption indicates largazole’s potential as drug lead for bone-related disorders, in addition to its potential as an anticancer drug. We are also evaluating largazole for other disease indications where cellular reprogramming of transcription may be beneficial. We also reported a process chemistry route to obtain deca-gram quantities of largazole for further preclinical studies.
Apratoxins are cytotoxic marine natural products that prevent cotranslational translocation early in the secretory pathway. We found that apratoxins downregulate receptor tyrosine kinases and their corresponding ligands, giving a one‒two punch to cancer cells, particularly those that rely on autocrine loops. Unfortunately, the parent compound apratoxin A displays irreversible toxicity; however, through a 21-step convergent total synthesis (35 steps total) we generated various analogues, one of which (apratoxin S4) has greater potency and selectivity for cancer cells in vitro and in vivo. Apratoxin S4 is a hybrid of natural apratoxins A and E, both of which we isolated from cyanobacteria and which provided the inspiration for this new synthetic molecule. Apratoxin S4 showed efficacy in a colorectal tumor xenograft mouse model without irreversible toxicity, demonstrating that its mechanism of action has therapeutic potential. Because of its potent angiogenic activity, we repurposed this compound as a treatment option for ocular angiogenic diseases. Further improvement to the stability and synthesis led to apratoxin S10 which in addition to its anticancer and antiangiogenic activity can also modulate the tumor microenvironment. Apratoxin S10 showed efficacy in an orthotopic patient-derived xenograft model for pancreatic cancer.
- Qiu, B.; Tan, A.; Veluchamy, A. B.; Li, Y.; Murray, H.; Cheng, W.; Liu, C.; Busoy, J. M.; Chen, Q.-Y.; Sistla, S.; Hunziker, W.; Cheung, C. M. G.; Wong, T. Y.;* Hong, W.;* Luesch, H.; Wang, X. “Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases” Ophthalmol. Vis. Sci. 2019, 60, 3254–3263. ncbi.nlm.nih.gov/pubmed/31361305
- Liang, X.; Luo, D.; Yan, J.-L.; Rezaei, M. A.; Salvador-Reyes, L. A.; Gunasekera, S. P.; Li, C.; Ye, T.; Paul, V. J.; Luesch, H. “Discovery of Amantamide, a Selective CXCR7 Agonist from Marine Cyanobacteria” Lett. 2019, 21, 1622–1626. ncbi.nlm.nih.gov/pubmed/30779584
- Cai, W.; Ratnayake, R.; Gerber, M. H.; Chen, Q.-Y.; Yu, Y.; Derendorf, H.; Trevino, J. G.; Luesch, H. “Development of Apratoxin S10 (Apra S10) as an Anti-Pancreatic Cancer Agent and Its Preliminary Evaluation in an Orthotopic Patient-Derived Xenograft (PDX) Model” New Drugs 2019, 37, 364–374. ncbi.nlm.nih.gov/pubmed/30073464
- Chen, Q.-Y.; Chaturvedi, P. R.; Luesch, H. “Process Development and Scale-up Total Synthesis of Largazole, a Potent Class I Histone Deacetylase Inhibitor” Process Res. Dev. 2018, 22, 190–199. https://pubs.acs.org/doi/full/10.1021/acs.oprd.7b00352
- Cai, W.; Salvador-Reyes, L. A.; Zhang, W.; Chen, Q.-Y.; Matthew, S.; Ratnayake, R.; Seo, S. J.; Dolles, S.; Gibson, D. J.; Paul, V. J.; Luesch, H. “Apratyramide, a Marine-Derived Peptidic Stimulator of VEGF-A and Other Growth Factors with Potential Application in Wound Healing” ACS Chem. Biol. 2018, 13, 91–99. ncbi.nlm.nih.gov/pubmed/29205032
- Cai, W.; Chen, Q.-Y.; Dang, L. H.; Luesch, H. “Apratoxin S10, a Dual Inhibitor of Angiogenesis and Cancer Cell Growth To Treat Highly Vascularized Tumors” ACS Med. Chem. Lett. 2017, 18, 1007–1012. ncbi.nlm.nih.gov/pubmed/29057042
- Wu, P.; Cai, W.; Chen, Q.-Y.; Xu, S.; Yin, R.; Li, Y.; Zhang, W.; Luesch, H. “Total Synthesis and Biological Evaluation of Apratoxin E and Its C30 Epimer: Configurational Reassignment of the Natural Product” Lett. 2016, 18, 5400–5403. ncbi.nlm.nih.gov/pubmed/27723359
- Gunasekera, S. P.; Li, Y.; Ratnayake, R.; Luo, D.; Lo, J.; Reibenspies, J. H.; Xu, Z.; Clare-Salzler, M. J.; Ye, T.; Paul, V. J.; Luesch, H. “Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Dimer from Marine Cyanobacteria” Eur. J. 2016, 22, 8158–8166. ncbi.nlm.nih.gov/pubmed/27139508
- Luo, D.; Chen, Q.-Y.; Luesch, H. “Total Synthesis of the Potent Marine-Derived Elastase Inhibitor Lyngbyastatin 7 and in Vitro Biological Evaluation in Model Systems for Pulmonary Diseases” Org. Chem. 2016, 81, 532–544. ncbi.nlm.nih.gov/pubmed/26709602
- Kim, B.; Park, H.; Salvador, L. A.; Serrano, P. E.; Kwan, J. C.; Zeller, S. L.; Chen, Q.-Y.; Ryu, S.; Liu, Y.; Byeon, S.; Luesch, H.; Hong, J. “Evaluation of Class I HDAC Isoform Selectivity of Largazole Analogues” Med. Chem. Lett. 2014, 24, 3728‒3731. ncbi.nlm.nih.gov/pubmed/25070421
- Salvador, L. A.; Park, H.; Al-Awadhi, F. H.; Liu, Y.; Kim, B.; Zeller, S. L.; Chen, Q.-Y.; Hong, J.; Luesch, H. “Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties” ACS Med. Chem. Lett. 2014, 5, 905‒910. ncbi.nlm.nih.gov/pubmed/25147612
- Chen, Q.-Y.; Liu, Y.; Cai, W.; Luesch, H. “Improved Total Synthesis and Biological Evaluation of Potent Apratoxin S4 Based Anticancer Agents with Differential Stability and Further Enhanced Activity” Med. Chem. 2014, 57, 3011‒3029. ncbi.nlm.nih.gov/pubmed/24660812
- Yu, M.; Salvador, L. A.; Sy, S. K. B.; Tang, Y.; Singh, R. S. P.; Chen, Q.-Y.; Liu, Y.; Hong, J.; Derendorf, H.; Luesch, H. “Largazole Pharmacokinetics in Rats by LC-MS/MS” Drugs 2014, 12, 1623‒1640. ncbi.nlm.nih.gov/pubmed/24658499
- Liu, H.; Liu, Y.; Wang, Z.; Xing, X.; Maguire, A. R.; Luesch, H.; Zhang, H.; Xu, Z.; Ye, T. “Total Synthesis and Biological Evaluation of Grassypeptolide A” Eur. J. 2013, 19, 6774‒6784. ncbi.nlm.nih.gov/pubmed/23536467
- Hong, J.; Luesch, H. “Largazole: From Discovery to Broad-Spectrum Therapy” Prod. Rep. 2012, 29, 449‒456. ncbi.nlm.nih.gov/pubmed/22334030
- Chen, Q.-Y.; Liu, Y.; Luesch, H. “Systematic Chemical Mutagenesis Identifies a Potent Novel Apratoxin A/E Hybrid with Improved in Vivo Antitumor Activity” ACS Med. Chem. Lett. 2011, 2, 861‒865. ncbi.nlm.nih.gov/pubmed/22081789
- Lee, S.-U.; Kwak, H. B.; Pi, S.-H.; You, H.-K.; Byeon, S. R.; Ying, Y.; Luesch, H.; Hong, J.; Kim, S. H. “In Vitro and In Vivo Osteogenic Activity of Largazole” ACS Med. Chem. Lett. 2011, 2, 248‒251. ncbi.nlm.nih.gov/pubmed/21666868
- Liu, Y.; Salvador, L. A.; Byeon, S.; Ying, Y.; Kwan, J. C.; Law, B. K.; Hong, J.; Luesch, H. “Anticolon Cancer Activity of Largazole, a Marine-Derived Tunable Histone Deacetylase Inhibitor” Pharmacol. Exp. Ther. 2010, 335, 351–361. ncbi.nlm.nih.gov/pubmed/20739454
- Ying, Y.; Liu, Y.; Byeon, S. R.; Kim, H.; Luesch, H.; Hong, J. “Synthesis and Activity of Largazole Analogues with Linker and Macrocycle Modification” Lett. 2008, 10, 4021–4024. ncbi.nlm.nih.gov/pubmed/18707106
- Ying, Y.; Taori, K.; Kim, H.; Hong, J.; Luesch, H. “Total Synthesis and Molecular Target of Largazole, a Histone Deacetylase Inhibitor” Am. Chem. Soc. 2008, 130, 8455–8459. ncbi.nlm.nih.gov/pubmed/18507379
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