Synthesis, DNA cleavage, and cytotoxicity of a series of bis(propargylic) sulfone crown ethers.
Compounds that couple molecular recognition of specific alkali metal ions with DNA damage may display selective cleavage of DNA under conditions of elevated alkali metal ion levels reported to exist in certain cancer cells. We have prepared a homologous series of compounds in which a DNA reactive moiety, a bis(propargylic) sulfone, is incorporated into an alkali metal ion binding crown ether ring. Using the alkali metal ion pricrate extraction assay, the ability of these crown ethers to bind Li(+), Na(+), and K(+) ions was determined. For the series of crown ethers, the association constants for Li(+) ions are generally low (< 2 x 10(4)M(-1)). Only two of the bis(propargylic) sulfone crown ethers associate with Na(+) or K(+) ions (K(a) 4-8 x 10(4)M(-1)), with little discrimination between Na(+) or K(+) ions. The ability of these compounds to cleave supercoiled DNA at pH 7.4 in the presence of Li(+), Na(+), and K(+) ions was determined. The two crown ethers that bind Na(+) and K(+) display a modest increase in DNA cleavage efficiency in the presence of Na(+) or K(+) ions as compared to Li(+) ions. These two bis(propargylic) sulfone crown ethers are also more cytotoxic against a panel of human cancer cell lines when compared to a non-crown ether macrocyclic bis(propargylic) sulfone.
McPhee
M M
MM
Division of Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, 78712, USA.
Kerwin
S M
SM
D000480:Alkynes; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002412:Cations / Q000737:chemistry; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004988:Ethers, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008670:Metals / Q000737:chemistry; D013329:Structure-Activity Relationship; D013450:Sulfones; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000480:Alkynes; D000970:Antineoplastic Agents; D002412:Cations; D004988:Ethers, Cyclic; D008670:Metals; D013450:Sulfones