▪ Independent Research at the University of Texas at El Paso (since fall 2015):
9. A One-Step Facile, Green and Gram-Scale Synthesis of Remdesivir's Nucleobase Developed during the Pandemic. Yaoqiu Zhu* To be submitted

 
 
10. Solving the Anti-COVID-19 Drug Supply Crisis. A Facile and Succinct New Route to Remdesivir Developed during the Pandemic. Yaoqiu Zhu*, Elkin L. Romero, Giber Fonseca. Under preparation

   

1. Nature Communications 2018, 9, 3952. [link] Clopidogrel as a Donor Probe and Thioenol Derivatives as Flexible Promoieties for Enabling H2S Biomedicine. Yaoqiu Zhu*, Elkin L. Romero, Xiaodong Ren, Angel J. Sanca, Congkuo Du, Cai Liu, Zubair A. Karim, Fatima Z. Alshbool, Fadi T. Khasawneh, Jiang Zhou, Dafang Zhong, Bin Geng

Abstract: Hydrogen sulfide has emerged as a critical endogenous signaling transmitter and a potentially versatile therapeutic agent. The key challenges in this field include the lack of approved hydrogen sulfide-releasing probes for in-human exploration and the lack of controllable hydrogen sulfide promoieties that can be flexibly installed for therapeutics development. Here we report the identification of the widely used antithrombotic drug clopidogrel as a clinical hydrogen sulfide donor. Clopidogrel is metabolized in patients to form a circulating metabolite that contains a thioenol substructure, which is found to undergo spontaneous degradation to release hydrogen sulfide. Model studies demonstrate that thioenol derivatives are a class of controllable promoieties that can be conveniently installed on a minimal structure of ketone with an alpha-hydrogen. These results can provide chemical tools for advancing hydrogen sulfide biomedical research as well as developing hydrogen sulfide-releasing drugs.
   

2. Bioinspired 3D Printing of Complex Natural Scaffold for Anticancer Lead Discovery: 4-Step Facile Total Synthesis of False-Bioactive (−)-Pavidolide B and Its Anticancer Stereoisomers. Yaoqiu Zhu*, Elkin L. Romero, Srinivas Kolluru, Elizabeth Noriega, Denisse A. Gutierrez, Renato Aguilera, Xin Yu, Anyi Wang, Jin Wang. 2021, under review. ChemRxiv preprint (prior version) DOI: https://doi.org/10.26434/chemrxiv.11560137.v1

Abstract: (−)-Pavidolide B is a complex 6/5/5/7 tetracyclic marine diterpenoid initially reported for its attractive anticancer selectivity. Challenging total syntheses have recently been accomplished to confirm the natural product is indeed inactive. In this work, a bioinspired annulation strategy of carbanion cascade reaction is formulated for achieving a protecting-group-free total synthesis of this natural product in just 4 facile linear steps. The key reaction is a tandem intramolecular Michael addition, which constructs two 5-membered rings and five stereocenters in a highly selective fashion in just one step. The expedient route has allowed us to '3D-print' three stereoisomers of the natural product, and they have demonstrated modest and distinctive anticancer activities in cell line studies across two laboratories. This work showcases that facile and flexible synthetic access to complex marine natural products can be developed for facilitating drug discovery.

   

3. First and Stereoselective Chemical Synthesis of Clopidogrel Active Metabolite for Directly Addressing Clinical Antithrombotic Conundrums. Yaoqiu Zhu*, Elkin L. Romero, Suresh Kurhade, Xiaodong Ren, Mingming Zhang, Zubair A. Karim, Fatima Z. Alshbool, Fadi T. Khasawneh, Jiang Zhou. 2021, manuscript submitted

Abstract: Despite of being one of the most prescribed medicines in history, the serendipitous prodrug clopidogrel (CPG) remains to be the mysterious and problematic antiplatelet to patients and a puzzling and formidable subject to researchers. The elusive active metabolite of CPG, H4, is reactive and unstable, and its structure and mechanism of action have yet to be fully elucidated. On the other hand, clinical CPG treatment has been associated with a daunting level of resistances, which is due to the fact that large populations of patients cannot metabolize it to H4. The lack of comprehensive response predictives and superior treatment alternatives, together with the life-threatening nature of thrombotic ischemia, have made H4 a high-profile synthetic target. However, the long pursuit of the intricate degradation structure proves to be challenging and remains unsolved. Here we report a 10-step stereoselective synthesis of H4 that is enabled by nontraditional approaches. The synthetic H4 and its three diastereomers, together with their stabilized derivatives, have been confirmed to be identical to the putative bioactivation references. With an experimentally established (4R)-configuration, H4 is tested to be the active metabolite of CPG in vivo for the first time. Flexible derivatization procedures are also developed to convert H4 to its stable mixed disulfide forms for facile release. The accomplishment of H4 synthesis can not only directly address the unmet clinical antithrombotic needs but also open doors to treating many other diseases. This work represents an inspiring example of organic synthesis in its direct impacts on clinical medicine.
   

4. A Facile Total Synthesis of the Caged Alkaloid Arboridinine Enabled by a Novel Annelation Strategy. Yaoqiu Zhu* manuscript under finalization
   

5. Model Pharmacology Study of Clopidogrel Active Metabolite Unveils New Chemistry of Mercapto Activation for Protein Persulfidation. Yaoqiu Zhu*, et al., manuscript under finalization

Abstract: The serendipitous prodrug clopidogrel (CPG) has been prevalently used in clinic despite of prominent therapeutic resistances and mysterious mechanism of drug action. Recently we accomplished the first and stereoselective synthesis of CPG active metabolite, H4, and our synthetic approaches have prompted us to investigate the antagonism mechanism of H4 on platelet membrane-bound G-protein coupled P2Y12 receptor. In this report, rational model studies are conducted for revealing unprecedented “on and off” reactivities of H4 against thiol reagents. Our results support that the bioactivated substructure of H4 can react with two cysteine residues (C97 and C175) in the extracellular pocket of the receptor in a stepwise manner, and the resulting modification such as protein persulfidation leads to the observed receptor disruption and translocation. The model study results and analyses can not only prompt re-evaluation and reconciliation of the results obtained from previous studies and but also guide the design of new experiments to fully elucidate the unique drug action of CPG. The unveiled structural insights can also be utilized in molecular design of chemical probes or therapeutics for the explorations of protein modification and regulation.
   
6. Reinvestigation of Clopidogrel Bioactivation Unveils New Cytochrome P450-Catalyzed Thioester Cleavage Mechanism. [link] Yaoqiu Zhu*, Jiang Zhou, Elkin L. Romero. Bioorg. Med. Chem. Lett. 2022, 72, 128872. Dr. Richard Silverman Honour Issue

Abstract: The serendipitous prodrug clopidogrel (CPG, M0) is the mainstay antiplatelet drug in clinical use. The thiophene moiety of CPG undergoes ring opening to form the active metabolite (M13) through two steps of cytochrome P450 (CYP)-catalyzed oxidation. The stable intermediate resulting from the first oxidation, 2-oxo-CPG (M2), is proposed to be oxidized to form an S-oxide intermediate (M11), which proceeds with a hydrolytic pathway to yield a sulfenic acid (M12) and subsequently the bioreduced active metabolite (M13). To test the long-standing pathway of M2 to M13 via M11, we have chemically synthesized M11 but found it does not undergo the proposed hydrolytic activation in various conditions including in liver microsomal incubations. To seek an alternative mechanism, 18O tracing studies were performed with both H218O and 18O2, and LC-MS studies show that the carboxylate product moiety acquires its O-atom from oxygen instead of water, which rules out M11 as the bioactivation intermediate. To explain the 18O tracing results, a one-step Baeyer-Villiger-like mechanism is proposed for the CYP-dependent thioester cleavage, which features the incorporation of the two O-atoms of O2 into the two product moieties of carboxylate and sulfenic acid. The research presented herein provides a biochemical basis for delineating the clinical pharmacology of a mainstay treatment and expands our understanding of CYP catalysis.
   

7. A Ligand-Directed Mutagenesis Approach for Inhibiting the Polymerization of alpha,beta-Tubulin Heterodimers. Yaoqiu Zhu*, Laura Diaz-Martinez, Angel J. Sance, Corinne R. Ley, et al. manuscript under preparation
   

8. 5-Step Total Synthesis of (±)-Maoecrystal V for Solving Its Anticancer Mystery. Yaoqiu Zhu* manuscript under preparation
   

  The mechanistic role of lung cancer-specific enzyme in acquired resistances of clinical tyrosine kinase inhibitors. Yaoqiu Zhu*, et al. manuscript under preparation
  Reactive Fragment Hopping Guided Development of Irreversible Antimitotic Inhibitors.Yaoqiu Zhu*, et al. manuscript under preparation
. Assemblies of Wafarin with Thioenol: Coactivation of Drug Recovery and H2S Release Confers Antithrombotic Synergism in Rat Models.
Yaoqiu Zhu*, et al. manuscript under preparation
  The Bigger-than-You-Think Orbital Interaction (Conjugation) Effects between Nonadjacent Atoms
Yaoqiu Zhu*, Jiang Zhou, Angel J. Sanca, Elizabeth Noriega manuscript under development
  Mechanistic Studies of Cytochrome P450-dependent Thioester Cleavage Reveal New Heme Chemistry
Yaoqiu Zhu*, et al. manuscript under development
▪ Independent Research at MetabQuest Research Laboratory:

5. Yaoqiu Zhu*, Jiang Zhou, and Bo Jiao, ACS Med. Chem. Lett. 2013, 4, 349-352. [link]
“Deuterated Clopidogrel Analogues as a New Generation of Antiplatelet Agents”

4. Yaoqiu Zhu* and Jiang Zhou, Chem. Res. Toxicol. 2013, 26, 179-190. [link]
“In Vitro Biotransformation Studies of 2-Oxo-clopidogrel: Multiple Thiolactone Ring Opening Pathways Further Attenuate Prodrug Activation”
3. Yaoqiu Zhu* and Jiang Zhou, ACS Med. Chem. Lett. 2012, 3, 844-849. [link]
“Identification of the Significant Involvement and Mechanistic Role of CYP3A4/5 in Clopidogrel Bioactivation”

2. Yinan Zhang, Radhia Benmohamed, Wei Zhang, Yaoqiu Zhu, Richard I. Morimoto, Robert J. Ferrante, Donald R. Kirsch, Richard B. Silverman, ACS Med. Chem. Lett. 2012, 3, 584-587. [link]
“Chiral Cyclohexane 1,3-Diones as Inhibitors of Mutant SOD1-dependent Protein Aggregation for the Treatment of Amyotrophic Lateral Sclerosis”
1. Jiaqi Shan, Boyu Zhang, Yaoqiu Zhu, Bo Jiao, Weiyi Zheng, Xiaowei Qi, Yanchun Gong, Fang Yuan, Fusheng Lv, and Hongbin Sun,
J. Med. Chem. 2012, 55, 3342-3352. [link]
“Overcoming Clopidogrel Resistance: Discovery of Vicagrel as A Highly Potent and Orally Bioavailable Antiplatelet Agent”
▪ Doctoral Research at Northwestern University:
4. Yaoqiu Zhu and Richard B. Silverman, Biochemistry 2008, 47, 2231-2243. [link]
“Revisiting Heme Mechanisms. A Perspective on the Mechanisms of Nitric Oxide Synthase (NOS), Heme Oxygenase (HO), and Cytochrome P450s (CYP450s)”
3. Yaoqiu Zhu and Richard B. Silverman, Org. Lett. 2007, 9, 1195-1198. [link]
“Model Studies for the Mechanism of Heme Oxygenase-Catalyzed Hydroxylation”
2. Yaoqiu Zhu and Richard B. Silverman, J. Org. Chem. 2007, 72, 233-239. [link]
“Electronic Effects of Peripheral Substituents on Porphyrin Meso Positions”
1. Yaoqiu Zhu, Dejan Nikolic, Richard B. van Breeman, and Richard B. Silverman, J. Am. Chem. Soc. 2005, 127, 858-868. [link]
“Mechanism of Inactivation of Inducible Nitric Oxide Synthase by Amidines. Irreversible Enzyme Inactivation without Inactivator Modification”