Ursolic Acid Conjugates: A New Frontier in Anticancer Drug Development

Riham M. Bokhtia, Ashley M. Pham, Kunj Bihari Gupta, Shamta S. Warang, Natasha Venugopal, Rajeev Shakuja, Payaningal R. Somanath, Fang Liu, Yi Chang Jeon, Guilherme J. Guimaraes, Michael G. Bartlett, Muthusamy Thangaraju, Bal L. Lokeshwar, Siva S. Panda

Research output: Contribution to journalArticlepeer-review

Abstract

New Ursolic Acid (UA) conjugates were synthesized using optimized synthetic protocols through the molecular hybridization approach at C-3 and C-28. This resulted in the targeted molecules being produced in good yields. Some of the synthesized conjugates showed significantly relevant bioactivity against mammalian cells and in animal models of cancers. Selected UA conjugates were tested against bladder and breast cancer cell lines. The conjugates showed moderate to significantly enhanced antiproliferative activities against Triple Negative Breast Cancer (TNBC; MDA-MB 231), which is an aggressive tumor making up about 10–15 % of all breast cancers and bladder (T24 and 5637) cancer cell lines. These properties were superior to the parent UA. Among all the synthesized compounds, 18 c and 18 d have exhibited promising antiproliferative and cytotoxic properties against all tested cancer cell lines. However, 18 d has proved to be exceptionally selective for cancer cell lines, showing more cytotoxicity towards them than normal epithelial cells (MCF-12A). Compound 18 d has demonstrated cytotoxicity against tumor cells, including those intrinsically resistant to chemotherapy drugs such as 2-difluoro-deoxy cytidine (Gemcitabine). The activity of the UA conjugates on tumor cells was mediated by multiple cytotoxic mechanisms, including drug-induced cytotoxic autophagy and programmed cell death, indicating a novel possibility of combination therapy.

Original languageEnglish (US)
Article numbere202400376
JournalChemBioChem
Volume25
Issue number20
DOIs
StatePublished - Oct 16 2024

Keywords

  • Bladder cancer
  • Breast cancer
  • Computational studies
  • Molecular hybridization
  • Natural product
  • Synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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