Fathi Halaweish Research
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 NMR, mass spectrometry (MS) 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.
- Design and synthesis of cancer chemotherapeutics targeting liver, lung, colon, pancreas, prostate, ovarian and 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 Americans medicine.
- Extraction and quantification of natural products from naturally occurring sources.
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 towards both 2-dimensional and 3-dimensional 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 most deadliest 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 (EGFR) 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 (HCC). 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 EGFR 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.
Publications List
- Estrone analogs as potential inhibitors targeting EGFR-MAPK pathway in non-small cell lung cancer. Chemical Biology and Drug Design. 2023, 1-11.
- Acheampong, F.; Ostlund, T.; Mahnashi, M.; Halaweish, F.
- Novel EGFR-MAPK Kinase and ABC Transporter Inhibitors for HepG2 Resistant to Erlotinib. Drug Discovery Research. 2023, 84, 200-210.
- Ostlund, T.; SutraDhar, K.; Elgazwi, S.; Mahnashi, M.; Kyeremateng, J.; Iram, S.; Halaweish, F.
- Triazole-estradiol analogs: A potential cancer therapeutic targeting ovarian and colorectal cancer. Steroids 2022, 177, 108950.
- Ostlund, T.; Alotaibi, F.; Kyeremateng, J.; Halaweish, H.; Kasten, A.; Iram, S.; Halaweish, F.
- Novel Mechanistic Insight into the Anticancer Activity of Cucurbitacin D against Pancreatic Cancer (Cucurbitacin D Attenuates Pancreatic Cancer). Cells 2020, 9, 103.
- M. Sikander, S. Malik, S. Khan, S. Kumari, N. Chauhan, P. Khan, F. T. Halaweish, B. Chauhan, M. M. Yallapu, M. Jaggi, S. C. Chauhan
- "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.
- Mahrous A. Abou-Salim, Mohamed A. Shaaban, Mohammed K. Abd El Hameid, Yaseen A.M.M. Elshaier, Fathi Halaweish
- "Cucurbitacins inspired organic synthesis: Potential dual inhibitors targeting EGFR–MAPK pathway." European Journal of Medicinal Chemistry 173, 294-304, 2019.
- Mater Mahnashi, Sara M. Elgazwi, Mahmoud Salama Ahmed, Fathi T. Halaweish
- "Cucurbitacin d reprograms glucose metabolic network in prostate cancer." Cancers 11, 364, 2019.
- Mohammed Sikander, Shabnam Malik, Neeraj Chauhan, Parvez Khan, Sonam Kumari, Vivek Kumar Kashyap, Sheema Khan et al
- "Isolation of anticancer constituents from Cucumis prophetarum var. prophetarum through bioassay-guided fractionation." BMC complementary and alternative medicine 18, 274-, 2018.
- Abdulrhman Alsayari, Lucas Kopel, Mahmoud Salama Ahmed, Hesham S. M. Soliman, Sivakumar Annadurai, Fathi T. Halaweish
- "The role of cucurbitacins in combating cancers: A mechanistic review." Pharmacognosy Reviews, 42,157-165, 2018.
- Abdulrhman Alsayari, Fathi Halaweish, Narasimman Gurusamy
- Cucurbitacin B Restored Cisplatin Sensitivity of Ovarian Cancer Cells by altering Fatty Acid Synthase and LRP-130 Protein Expression, CPQ Cancer, 1(4) 2018.
- F. El-Senduny, F. Badria, A. El-Waseef, S. Chauhan, F. Halaweish
- 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.
- Rania S.M., Wagdy M. Eldehna, Nasser S.M. Ismail, Sara M. Elgazwi, Hazem A. Ghabbour, Mahmoud Salama Ahmed, Fathi T. Halaweish, Dalal A. Abou El Ella
- 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.
- 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, Meena Jaggi
- Design and synthesis of pyrazolo[3, 4-d]pyrimidines: Nitric oxide releasing compounds targeting hepatocellular carcinoma, Bioorganic and Medicinal Chemistry, 25, 2956-2970, 2017.
- Yaseen A. M. M. Elshaier, Mohamed A. Shaaban, Mohammed K. Abd El Hamid, Mostafa H. Abdelrahman, Mahrous A. Abou-Salim, Sara M. Elgazwi, Fathi Halaweish
- Biological Screening of Cucurbitacin Inspired Estrone Analogs Targeting Mitogen Activated Protein Kinase (MAPK) Pathway, Chemistry, Biology and Drug Design, 90, 478-484, 2017.
- M. S. Ahmed, F. El-Senduny, J. Taylor, F. Halaweish
- Mechanistic investigation of hepato-protective potential for cucurbitacins, Med Chem Res 26,1567, 2017.
- H. M. Arjaibi, M. S. Ahmed, F. T. Halaweish
- Design, Synthesis and Biological Evaluation of Steroidal Analogs as estrogenic / anti-estrogenic agents, Steroids, 118, 32–40, 2017.
- A. Alsayari, L. Kopel, M. S. Ahmed, A. Pay, T. Carlson, F. Halaweish
- Cucurbitacin D exhibits potent anti-cancer activity in cervical cancer, Scientific Reports, 6, 2016.
- M. Sikander, B. Bin Hafeez, S. Malik, A. Alsayari, F. Halaweish, M. Yallapu, C. Subhash, S. Chauhan, M. Jaggi
- Assessment of Chemopreventive Contents of Native American Juneberries (Amelanchier alnifolia (Nutt.) Nutt. ex M. Roem.), Pharmaceutical crops,10, 13-21, 2016.
- Shimara Gunawardana, Keeli Eberhart, Kerry Hartman1, Fathi T. Halaweish
- Approach for chemosensitization of cisplatin-resistant ovarian cancer by cucurbitacin B, Tumor Biology, 37, 685–698, 2016.
- F. El-Senduny, F. Badria, A. El-Waseef, S. Chauhan and F. Halaweish
- Nanoparticle formulation of ormeloxifene for pancreatic cancer, Biomaterials, 53, 731-743, 2015.
- P. Balabathula, A. Swathi, N. Zafar, P. Thompson, R. T. Ellis, F. Halaweish, S. Chauhan, M. Jaggi, Sheem Khan
- Cucurbitacin D is a disruptor of the hsp90 chaperone machinery, Journal of Natural Products, J. Nat. Prod., March 10, 2015.
- J. Hall, N. Rice, I. Kopel, F. Halaweish, B. Blagg
- Ormeloxifene efficiently inhibits ovarian cancer growth, Cancer Letters, 356, 606–612, 2015.
- 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, Subhash C. Chauhan
- Structural Optimization and Biological Screening of a Steroidal Scaffold Possessing Cucurbitacin-Like Functionalities as B-Raf Inhibitors, ChemMedChem, 9, 1361-1369, 2014.
- Mahmoud S. Ahmed, Lucas C. Kopel, Fathi Halaweish
- Design, Synthesis and In vitro Anti-tumor Evaluation of Novel Acrylohydrazide Thioglycosides; Med. Chem. 4, 400-406, 2014.
- Galal H. Elgemeie, Nahed M. Fathy, Ayman B. Farag, Ossama M. El-Badry, Ghaneia S. Hassan, Kamelia M Amin, Fathi Halaweish
Drug Discovery
Recent group accomplishments in drug discovery include:
- Synthesis of novel steroidal analogs that have shown promising activity toward BRAF-MEK signaling mechanisms.
- Synthesis of novel cucurbitacins and hexanor analogs as potential candidate for treatment of prostate cancer.
- 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.
- 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)
The National Science Foundation partners with several universities to host a small group of students to participate in a research projects while working with faculty members of the university. Many of these programs are 10 week summer programs as to not interfere with students' undergraduate studies. Students may be offered a stipend, housing and/or travel assistance. Application processes are determined by the host university, but are usually free and open to any US citizens/residents. These are wonderful experiences for undergraduates wanting to gain research experiences, as well as explore other institutions.
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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 South à£à£Ö±²¥Ðã State University 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.
Meet the Research Group!
Degree: Pursuing Ph.D. Degree (Fourth Year)
From: Bangladesh
Career Interest: Trying to develop a drug like compound for prostate cancer or Alzheimer 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@jacks.sdstate.edu
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 Junior
Major in Human Biology
From Sioux Falls
Career interests: Pre-Medicine
Major: Chemistry and Biochemistry
From: Ituzaingo, Buenos Aires, Argentina
Career Interests: Organic chemistry with a focus in synthesis
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 PA program.
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.
Ph.D. in Chemistry
From: Sioux Falls
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.
Bachelor's in Chemistry
Bachelor's in Biochemistry
From: Yankton, SD
Career Interests: Working with research. Currently working for POET and planning to go to graduate school.