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Fathi Halaweish Research

Research Summary

My group conducts research on the structural, synthetic and medicinal chemistry of natural products, as well as optimization of analogs derived from natural products. This includes molecular modeling, molecular dynamics, chemical and biological investigation, and methods development for drug discovery of exceedingly small amounts of rare natural products using nuclear magnetic resonance, mass spectrometry and synthesis of drug-like analogs for therapeutic areas using in silico approaches.

We have developed several drug candidates and expertise in hit-to-lead optimization (computational support and/or synthetic medicinal chemistry output) utilizing library analysis, analogue design and allosteric site identification.

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Interests
Research
  • Design and synthesis of cancer chemotherapeutics targeting liver, lung, colon, pancreas, prostate, ovarian, cervical and breast cancer.
  • Potential drug candidate studies targeting kinase and phosphatase inhibitors.
  • Molecular docking and molecular dynamic simulation studies for guided structure design.
  • Bioassay-guided separation, structure elucidation, synthesis and biotransformation of potential drug candidates.
  • Drug development and nutraceutical standardization of Native American medicine.
  • Extraction and quantification of natural products from naturally occurring sources.
Current Projects
Design and synthesis of C-11 substituted estrone analogs for treatment in pancreatic cancer
  • Pancreatic cancer remains one of the deadliest cancers particularly due to its sudden onset, fast progression and lack of a reliable treatment option. Recent studies from our laboratory have determined that substitution of estrone analogs at their C-11 position provides increased cytotoxicity toward both 2D and 3D cell cultures in-vitro. Recent work has focused on analogs with oxygenated and nitrogenous functionality.
Design and synthesis of fluorine-substituted aromatic estrone analogs for prostate cancer
  • Prostate cancer remains one of the deadliest cancers among men, with drug resistance to therapeutic being common. Current work in our laboratory details the substitution of aromatic steroids with fluorine atoms to increase binding to kinases involved in cell survival, namely the epidermal growth factor receptor pathway. Synthesis of first-round analogs is currently being investigated.
Synthetic optimization for substituted C23-C24 enone analogs for use in hepatocellular carcinoma
  • A large number of studies have been performed in our laboratory (see recent publications) regarding the use of estrone analogs in hepatocellular carcinoma. These analogs possess a potential flaw in that they exhibit the ability to act as Michael acceptors for conjugation addition. This could lead to fast metabolism and removal from the body, and as such is being investigated by exploring the ability to substitute the enone system with fluorine and nitrile functionalization. Synthetic optimization is currently being investigated.
Design and synthesis of C17-amino acid analogs for treatment in pancreatic cancer
  • With our recent success in developing C-11 amino analogs, we have begun work on functionalizing these groups on our steroid core at the C-17 position, a key location for bioactivity. Current work details installation of various amino acid functional groups to this amine to mimic a "protein conjugate" in hopes for increased bioactivity. Molecular modeling studies have suggested these analogs show improvement over previously synthesized analogs, and their synthesis is currently being performed.
Biological screening of triazole-estradiol analogs in triple-negative breast cancer and hepatocellular carcinoma
  • One set of compounds we have previously created, our triazole-estradiol analogs, showed the ability to revert drug resistance in ovarian and colorectal cancer cells by inhibition of key epidermal growth factor receptor pathway proteins. This work details the use of these analogs, as well as second-generation analogs, in other cancers such as triple-negative breast cancer and hepatocellular carcinoma. Current work is being performed to study the biological effects of these analogs in both cancers.
Determination and quantification of natural products in plant materials
  • Current work in our laboratory has also been investigating the roles of various plant metabolites in protecting the plant from environmental damages. Two projects in collaboration with other sites have detailed the extraction, isolation, determination and quantification of these plant metabolites from natural sources using high performance liquid chromatography systems.
Accomplishments
Drug Discovery

Recent group accomplishments in drug discovery include:

  1. Synthesis of novel steroidal analogs that have shown promising activity toward BRAF-MEK signaling mechanisms.
  2. Synthesis of novel cucurbitacins and hexanor analogs as potential candidate for treatment of prostate cancer.
  3. Synthesis of novel cucurbitane and estrone (anti-estrogenic drug candidates) based analogs for treatment of breast, pancreatic and ovarian cancers, as well as other diseases.
  4. Synthesis of novel inspired estrone analogs targeting hepatocellular carcinoma and kinase signaling pathways.
Teaching
  • Structural Determination of Organic Compounds Spectroscopy (Chemistry 724)
  • Molecular Modeling and Drug Design (Chemistry 691)
  • Natural Products Synthesis (Chemistry 722)
  • Organic Chemistry I and II (Chemistry 326 and 328)
Recent Publications
Past Publications
  1. "Estrone analogs as potential inhibitors targeting EGFR-MAPK pathway in non-small cell lung cancer." Chemical Biology and Drug Design. 2023, 1-11.
    1. Acheampong, F.; Ostlund, T.; Mahnashi, M. and Halaweish, F.
  2. "Novel EGFR-MAPK kinase and ABC transporter inhibitors for HepG2 resistant to erlotinib." Drug Discovery Research. 2023, 84, 200-210.
    1. Ostlund, T.; SutraDhar, K.; Elgazwi, S.; Mahnashi, M.; Kyeremateng, J.; Iram, S. and Halaweish, F.
  3. "Triazole-estradiol analogs: A potential cancer therapeutic targeting ovarian and colorectal cancer." Steroids 2022, 177, 108950.
    1. Ostlund, T.; Alotaibi, F.; Kyeremateng, J.; Halaweish, H.; Kasten, A.; Iram, S. and Halaweish, F.
  4. "Novel mechanistic insight into the anticancer activity of cucurbitacin D against pancreatic cancer (cucurbitacin D attenuates pancreatic cancer)." Cells 2020, 9, 103.
    1. M. Sikander, S. Malik, S. Khan, S. Kumari, N. Chauhan, P. Khan, F.T. Halaweish, B. Chauhan, M.M. Yallapu, M. Jaggi and S.C. Chauhan
  5. "Design, synthesis and biological study of hybrid drug candidates of nitric oxide releasing cucurbitacin-inspired estrone analogs for treatment of hepatocellular carcinoma." Bioorganic Chemistry 85, 515-533, 2019.
    1. Mahrous A. Abou-Salim, Mohamed A. Shaaban, Mohammed K. Abd El Hameid, Yaseen A.M.M. Elshaier and Fathi Halaweish
  6. "Cucurbitacins inspired organic synthesis: Potential dual inhibitors targeting EGFR-MAPK pathway." European Journal of Medicinal Chemistry 173, 294-304, 2019.
    1. Mater Mahnashi, Sara M. Elgazwi, Mahmoud Salama Ahmed and Fathi T. Halaweish
  7. "Cucurbitacin d reprograms glucose metabolic network in prostate cancer." Cancers 11, 364, 2019.
    1. Mohammed Sikander, Shabnam Malik, Neeraj Chauhan, Parvez Khan, Sonam Kumari, Vivek Kumar Kashyap and Sheema Khan et al
  8. "Isolation of anticancer constituents from Cucumis prophetarum var. prophetarum through bioassay-guided fractionation." BMC complementary and alternative medicine 18, 274-, 2018.
    1. Abdulrhman Alsayari, Lucas Kopel, Mahmoud Salama Ahmed, Hesham S.M. Soliman, Sivakumar Annadurai and Fathi T. Halaweish
  9. "The role of cucurbitacins in combating cancers: A mechanistic review." Pharmacognosy Reviews, 42, 157-165, 2018.
    1. Abdulrhman Alsayari, Fathi Halaweish and Narasimman Gurusamy
  10. "Cucurbitacin B restored cisplatin sensitivity of ovarian cancer cells by altering fatty acid synthase and LRP-130 protein expression," CPQ Cancer, 1(4) 2018.
    1. F. El-Senduny, F. Badria, A. El-Waseef, S. Chauhan and F. Halaweish
  11. "Novel series of 6-(2-substitutedacetamido)-4-anilinoquinazolines as EGFR-ERK signal transduction inhibitors in MCF-7 breast cancer cells." European Journal of Medicinal Chemistry, 155, 782-796, 2018.
    1. Rania S.M., Wagdy M. Eldehna, Nasser S.M. Ismail, Sara M. Elgazwi, Hazem A. Ghabbour, Mahmoud Salama Ahmed, Fathi T. Halaweish and Dalal A. Abou El Ella
  12. "Ormeloxifene suppresses prostate tumor growth and metastatic phenotypes via inhibition of oncogenic β-catenin signaling and EMT progression." Molecular Cancer Therapeutics, 16, 2267-2280, 2017.
    1. Bilal Bin Hafeez, Aditya Ganju, Mohammed Sikander, Vivek K. Kashyap, Zubair Bin Hafeez, Neeraj Chauhan, Shabnam Malik, Andrew E. Massey, Manish K. Tripathi, Fathi T. Halaweish, Nadeem Zafar, Man M. Singh, Murali M. Yallapu, Subhash C. Chauhan and Meena Jaggi
  13. "Design and synthesis of pyrazolo[3, 4-d]pyrimidines: Nitric oxide releasing compounds targeting hepatocellular carcinoma." Bioorganic and Medicinal Chemistry, 25, 2956-2970, 2017.
    1. Yaseen A.M.M. Elshaier, Mohamed A. Shaaban, Mohammed K. Abd El Hamid, Mostafa H. Abdelrahman, Mahrous A. Abou-Salim, Sara M. Elgazwi and Fathi Halaweish
  14. "Biological screening of cucurbitacin inspired estrone analogs targeting mitogen activated protein kinase (MAPK) pathway." Chemistry, Biology and Drug Design, 90, 478-484, 2017.
    1. M.S. Ahmed, F. El-Senduny, J. Taylor and F. Halaweish
  15. "Mechanistic investigation of hepato-protective potential for cucurbitacins." Medicinal Chemistry Research 26, 1567, 2017.
    1. H.M. Arjaibi, M.S. Ahmed and F.T. Halaweish
  16. "Design, synthesis and biological evaluation of steroidal analogs as estrogenic/anti-estrogenic agents." Steroids, 118, 32-40, 2017.
    1. A. Alsayari, L. Kopel, M.S. Ahmed, A. Pay, T. Carlson and F. Halaweish
  17. "Cucurbitacin D exhibits potent anti-cancer activity in cervical cancer." Scientific Reports, 6, 2016.
    1. M. Sikander, B. Bin Hafeez, S. Malik, A. Alsayari, F. Halaweish, M. Yallapu, C. Subhash, S. Chauhan and M. Jaggi
  18. "Assessment of chemopreventive contents of Native American juneberries (Amelanchier alnifolia (Nutt.) Nutt. ex M. Roem.)." Pharmaceutical Crops, 10, 13-21, 2016.
    1. Shimara Gunawardana, Keeli Eberhart, Kerry Hartman and Fathi T. Halaweish
  19. "Approach for chemosensitization of cisplatin-resistant ovarian cancer by cucurbitacin B," Tumor Biology, 37, 685-698, 2016.
    1. F. El-Senduny, F. Badria, A. El-Waseef, S. Chauhan and F. Halaweish
  20. "Nanoparticle formulation of ormeloxifene for pancreatic cancer." Biomaterials, 53, 731-743, 2015.
    1. P. Balabathula, A. Swathi, N. Zafar, P. Thompson, R.T. Ellis, F. Halaweish, S. Chauhan, M. Jaggi and Sheem Khan
  21. "Cucurbitacin D is a disruptor of the hsp90 chaperone machinery." Journal of Natural Products, March 10, 2015.
    1. J. Hall, N. Rice, I. Kopel, F. Halaweish and B. Blagg
  22. "Ormeloxifene efficiently inhibits ovarian cancer growth." Cancer Letters, 356, 606-612, 2015.
    1. Diane M. Maher, Sheema Khan, Jordan L. Nordquist, Mara C. Ebeling, Nichole A. Bauer, Lucas Kopel, Man Mohan Singh, Fathi Halaweish, Maria C. Bell, Meena Jaggi and Subhash C. Chauhan
  23. "Structural optimization and biological screening of a steroidal scaffold possessing cucurbitacin-like functionalities as B-Raf inhibitors." ChemMedChem, 9, 1361-1369, 2014.
    1. Mahmoud S. Ahmed, Lucas C. Kopel and Fathi Halaweish
  24. "Design, synthesis and in vitro anti-tumor evaluation of novel acrylohydrazide thioglycosides." Medical Chemistry 4, 400-406, 2014.
    1. Galal H. Elgemeie, Nahed M. Fathy, Ayman B. Farag, Ossama M. El-Badry, Ghaneia S. Hassan, Kamelia M. Amin and Fathi Halaweish
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Principal Investigator

Dr. Fathi Halaweish picture
Fathi Halaweish, Ph.D.
Principal Investigator

I have significant expertise in the research of novel pharmaceutical compounds inspired from organic natural products, including steroidal analogs similar to cholesterol and other sterols. We utilize computer modeling to predict the effect these analogs will have and, after synthesizing these analogs, test them in-vitro.

At ÈÕ±¾avÊÓƵ we have established a state-of-the-art infrastructure for drug discovery and analysis of molecular interactions in various biological systems. I have carried out multiple successful projects, while inspiring research programs through interdisciplinary and collaborative projects geared towards the development of novel pharmaceuticals, agrochemicals and drug interactions with nutraceutical preparations. I collaborate with multidisciplinary researches and have published peer-reviewed articles and submitted several patent applications from projects conducted in my group.

My research group consists of one graduate students and six undergraduate students. We are currently working on multiple projects to support our drug discovery processes and molecular interaction studies.

Contact Fathi Halaweish

Meet the Research Group!

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Kakan SutraDhar

Degree: Pursuing Ph.D. degree (fourth year)

From: Bangladesh

Career interest: Trying to develop a drug-like compound for prostate cancer or Alzheimer's disease in near future. To fulfill this goal, I want to go research and development position in the pharmaceutical industry as a scientist or senior scientist.

Contact Kakan Sutradhar

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Noe Aparicio

Senior undergraduate

Major: Chemistry
Minor: Biochemical

From: Santa Ana, California

Career interests: Interested in going into graduate school to do work in an organic chemistry/pharmaceutical setting.

Undergraduate student Emily H
Emily Hedge

Junior undergraduate

Major: Human biology

From: Sioux Falls, South Dakota

Career interests: Pre-medicine.

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Axel Irianni

Major: Chemistry and biochemistry

From: Ituzaingo, Buenos Aires, Argentina

Career interests: Organic chemistry with a focus in synthesis.

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Jaritza Cazares Cruz

Freshman undergraduate

Major: Biochemistry and human biology

From: Litchfield, Minnesota and Tijuana, Mexico

Career interests: I plan on going into the medical field whether that be going to medical school or a physician assistant program.

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Kiara Schilling

Major: Chemistry and biochemistry

From: Benson, Minnesota

Career interests: Work in a research capacity for the government where I can apply my skills to address important societal issues.

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Recent Graduate - Trevor Ostlund

Ph.D. in chemistry

From: Sioux Falls, South Dakota

Career interests: My research interests are focused in designing cancer therapeutics, primarily on the synthetic side of chemistry. I hope to work in academia someday.

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Recent Graduate: Olivia Warriner

Bachelor's in chemistry
Bachelor's in biochemistry

From: Yankton, South Dakota

Career interests: Working with research. Currently working for POET and planning to go to graduate school.