Article

Design, Synthesis, and Cytotoxicity of Novel 3‐Arylidenones Derived from Alicyclic Ketones

Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
Chemical Biology &amp Drug Design (Impact Factor: 2.51). 09/2011; 78(4):700 - 708. DOI: 10.1111/j.1747-0285.2011.01176.x

ABSTRACT Forty-four novel chalcone-inspired analogs having a 3-aryl-2-propenoyl moiety derived from alicyclic ketones were designed, synthesized, and investigated for cytotoxicity against murine B16 and L1210 cancer cell lines. The analogs belong to four structurally divergent series, three of which (series g, h, and i) contain differently substituted cyclopentanone units and the fourth (series j) contains a 3,3-dimethyl-4-piperidinone moiety. Of these, the analogs in series j showed potential cytotoxic activity against murine B16 (melanoma) and L1210 (lymphoma) cells. The most active compounds 5j, 11j, 15j, and 12h produced IC(50) values from 4.4 to 15 μm against both cell lines. A single-crystal X-ray structure analysis and molecular modeling studies confirmed that these chalcones have an E-geometry about the alkene bond and possess a slightly 'twisted' conformation similar to that of combretastatin A-4. At a concentration of 30 μm, compounds 5j, 11j, and 15j did not cause microtubule depolymerization in cells, suggesting that they have a different mechanism of action.

0 Followers
 · 
116 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: An extensive study of analogs of the potent antitumor antibiotics CC-1065 and the duocarmycins which incorporate the 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) alkylation subunit are detailed. In contrast to early speculation, deep-seated modifications in the CC-1065 and duocarmycin alkylation subunits are well tolerated and the CBI-based analogs proved to be potent cytotoxic agents and efficacious antitumor compounds. Full details of studies defining a direct relationship between functional stability and in vitro cytotoxic potency are described. As such, the readily accessible CBI-based analogs were found to be four times more stable and four times more potent than the corresponding analogs containing the authentic CPI alkylation subunit of CC-1065 and comparable in potency to agents containing the authentic alkylation subunit of duocarmycin SA. Similarly, the CBI-based agents alkylate DNA with an unaltered sequence selectivity at an enhanced rate and with a greater efficiency than the corresponding CPI analog and were comparable to the corresponding analog incorporating the duocarmycin SA alkylation subunit. Systematic and extensive modifications and simplifications in the DNA binding subunits attached to CBI were explored with the comparisons of both enantiomers of CC-1065 and the duocarmycins 2 and 3 with enantiomers of 18-24, 25-29, 57-61, 62-65, 66-68, 72, 73, 78 and 79.
    Bioorganic & Medicinal Chemistry 12/1995; 3(11):1429-53. DOI:10.1016/0968-0896(95)00130-9 · 2.95 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A practical synthesis of CBI (2), utilizing inexpensive starting materials, was developed and applied to the synthesis of benzannelated analogs of CC-1065, in particular CBI-PDE-I-dimer (13) and CBI-bis-indole (17). While a Sharpless asymmetric dihydroxylation reaction proved effective at providing optically active intermediates, a more classical resolution procedure was used to prepare materials of higher optical purity. A novel cyclization employing a six-membered-ring intermediate (12) was employed to construct the cyclopropyl ring in CBI. Like CC-1065, CBI-PDE-I-dimer appears to cause delayed toxicity in mice.
    The Journal of Organic Chemistry 04/2002; 57(23). DOI:10.1021/jo00049a035 · 4.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Three new chalcones, xanthoangelol I (1), xanthoangelol J (2), and deoxydihydroxanthoangelol H (3), were isolated from an ethyl acetate-soluble fraction of exudates of the stems of Angelica keiskei, and their structures were established on the basis of spectroscopic methods. Nine aromatic compounds of known structure, 4-12, and a diacetylene, 13, were also isolated and identified from this same fraction. On evaluation of these compounds for their inhibitory effects on the induction of Epstein-Barr virus early antigen (EBV-EA) by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells, 1, 2, 4, and 9-12 showed potent inhibitory effects on EBV-EA induction. In addition, upon evaluation of the inhibitory effects against activation of (+/-)-(E)-methyl-2[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a nitrogen oxide (NO) donor, six compounds, namely, 1, 2, 4, 9, 11, and 12, exhibited potent inhibitory effects. Further, isobavachalcone (4) exhibited inhibitory effects on skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter.
    Journal of Natural Products 02/2006; 69(1):38-42. DOI:10.1021/np058080d · 3.95 Impact Factor