title: Synthesis and biological evaluation of 2-alkoxycarbonylallyl esters as potential anticancer agents.
abstract: The reaction of carboxylic acids with Baylis-Hillman reaction derived α-bromomethyl acrylic esters readily provide 2-(alkoxycarbonyl)allyl esters in good to excellent yields. These functionalized allyl esters have been evaluated for their cell proliferation inhibition properties against breast cancer (MDA-MB-231 and 4T1) and pancreatic cancer (MIAPaCa-2) cell lines to explore their potential as anticancer agents. Several of the synthesized derivatives exhibit good potency against all three cancer cell lines. Our structure activity relationship (SAR) studies on 2-carboxycarbonyl allyl esters indicate that substituted aromatic carboxylic acids provide enhanced activity compared to substituted aliphatic carboxylic acid analogs. Di- and tri-allyl esters derived from di-and tri-carboxylic acids exhibit higher inhibition of cell proliferation than mono esters. Further SAR studies indicate that the double bond in the 2-(alkoxycarbonyl)allyl ester is required for its activity, and there is no increase in activity with increased chain length of the alkoxy group. Two lead candidate compounds have been identified from the cell proliferation inhibition studies and their preliminary mechanism of action as DNA damaging agents has been evaluated using epifluorescence and western blot analysis. One of the lead compounds has been further evaluated for its systemic toxicity in healthy CD-1 mice followed by anticancer efficacy in a triple negative breast cancer MDA-MB-231 xenograft model in NOD-SCID mice. These two in vivo studies indicate that the lead compound is well tolerated in healthy CD-1 mice and exhibits good tumor growth inhibition compared to breast cancer drug doxorubicin.
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States.
authors.forename: Conor T
authors.initials: CT
authors.lastname: Ronayne
authors.affiliation: Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States.
authors.forename: Lucas N
authors.initials: LN
authors.lastname: Solano
authors.affiliation: Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States.
authors.forename: Grady L
authors.initials: GL
authors.lastname: Nelson
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States.
authors.forename: Erica A
authors.initials: EA
authors.lastname: Lueth
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States.
authors.forename: Skyler L
authors.initials: SL
authors.lastname: Hubbard
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States.
authors.forename: Tanner J
authors.initials: TJ
authors.lastname: Schumacher
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States.
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Gardner
authors.affiliation: Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States.
authors.forename: Sravan K
authors.initials: SK
authors.lastname: Jonnalagadda
authors.affiliation: Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States.
authors.forename: Shirisha
authors.initials: S
authors.lastname: Gurrapu
authors.affiliation: Department of Biomedical Sciences, Medical School Duluth, University of Minnesota, Duluth, MN 55812, United States.
authors.forename: Jon
authors.initials: J
authors.lastname: Holy
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States; Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States; Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN 55812, United States. Electronic address: vmereddy@d.umn.edu.
authors.forename: Venkatram R
authors.initials: VR
authors.lastname: Mereddy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002264:Carboxylic Acids / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004952:Esters / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D004952:Esters; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: 2-Alkoxycarbonylallyl esters; Baylis-Hillman; Breast cancer; Bromomethyl acrylate; DNA alkylation; Karyorrhexis; PARP-1 activation; Pancreatic cancer; γ-H2AX