Synthesis and evaluation of anticancer benzoxazoles and benzimidazoles related to UK-1.
UK-1 is a structurally unique bis(benzoxazole) natural product isolated from a strain of Streptomyces. UK-1 has been reported to possess anticancer activity but no activity against bacteria, yeast, or fungi. Previous work has also demonstrated the ability of UK-1 to bind a variety of di- and tri-valent metal ions, particularly Mg(2+) ions, and to form complexes with double-stranded DNA in the presence of Mg(2+) ions. Here we report the activity of UK-1 against a wide range of human cancer cell lines. UK-1 displays a wide spectrum of potent anticancer activity against leukemia, lymphoma, and certain solid tumor-derived cell lines, with IC(50) values as low as 20 nM, but is inactive against Staphylococcus aureus, a methicillin-resistant strain of S. aureus, or Pseudomonas aeruginosa. A series of analogues of the bis(benzoxazole) natural product UK-1 in which the carbomethoxy-substituted benzoxazole ring of the natural product was modified were prepared and evaluated for their anticancer and antibacterial properties. An analogue of UK-1 in which the carbomethoxy-substituted benzoxazole ring was replaced with a carbomethoxy-substituted benzimidazole ring was inactive against human cancer cell lines and the two strains of S. aureus. In contrast, a simplified analogue in which the carbomethoxy-substituted benzoxazole ring was replaced with a carbomethoxy group was almost as active as UK-1 against the four cancer cell lines examined but lacked activity against S. aureus. Metal ion binding studies of these analogues demonstrate that they both bind Zn(2+) and Ca(2+) ions about as well as UK-1. The non-cytotoxic benzimidazole UK-1 analogue binds Mg(2+) ions 50-fold weaker than UK-1, whereas the simple benzoxazole analogue binds Mg(2+) ions nearly as well as UK-1. These results support a role of Mg(2+) ion binding in the selective cytotoxicity of UK-1 and provide a minimal pharmacophore for the selective cytotoxic activity of the natural product.
Kumar
Devinder
D
Division of Medicinal Chemistry and Institute of Cellular and Molecular Biology, College of Pharmacy, The University of Texas at Austin, 78712, USA.
Jacob
Melissa R
MR
Reynolds
Michael B
MB
Kerwin
Sean M
SM
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002412:Cations / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008274:Magnesium / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001583:Benzoxazoles; D002412:Cations; C082787:UK 1; D008274:Magnesium