ABSTRACT
Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263.
ABSTRACT
Bioassay-guided fractionation of two cyanobacterial extracts from Papua New Guinea has yielded hoiamide D in both its carboxylic acid and conjugate base forms. Hoiamide D is a polyketide synthase (PKS)/non-ribosomal peptide synthetase (NRPS)-derived natural product that features two consecutive thiazolines and a thiazole, as well as a modified isoleucine residue. Hoiamide D displayed inhibitory activity against p53/MDM2 interaction (EC(50)=4.5 µM), an attractive target for anticancer drug development.
Subject(s)
Cyanobacteria/metabolism , Depsipeptides/pharmacology , Neoplasms/drug therapy , Proto-Oncogene Proteins c-mdm2/metabolism , Thiazoles/chemical synthesis , Thiazolidines/chemical synthesis , Tumor Suppressor Protein p53/metabolism , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Isoleucine/chemistry , Magnetic Resonance Spectroscopy/methods , Models, Chemical , Ribosomes/metabolism , Thiazoles/chemistry , Thiazoles/pharmacology , Thiazolidines/pharmacologyABSTRACT
Examination of the saline fermentation products from the marine-derived ascomycete fungal strain CNL-523 (Cryptosphaeria sp.) resulted in the isolation of cryptosphaerolide (1). The new compound is an ester-substituted sesquiterpenoid related to the eremophilane class. The structure of the new compound was assigned by spectroscopic and chemical methods. Cryptosphaerolide was found to be an inhibitor of the protein Mcl-1, a cancer drug target involved in apoptosis. It also showed significant cytotoxicity against an HCT-116 human colon carcinoma cell line, indicating that the compound may be of value in exploring the Mcl-1 pathway as a target for cancer chemotherapy.
Subject(s)
Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Ascomycota/chemistry , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Amino Acid Sequence , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Bahamas , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , Marine Biology , Molecular Structure , Myeloid Cell Leukemia Sequence 1 Protein , Nuclear Magnetic Resonance, Biomolecular , Sesquiterpenes/chemistryABSTRACT
Bioactivity-guided fractionation of metabolites from the crinoid Holopus rangii led to the discovery of two new phenanthroperylenequinone derivatives, gymnochromes E (1) and F (2). Gymnochrome E showed cytotoxic activity toward the NCI/ADR-Res with an IC(50) of 3.5 microM. It also inhibited histone deacetylase-1 with an IC(50) of 3.3 microM. Gymnochrome F was a moderate inhibitor of myeloid cell leukemia sequence 1 (MCL-1) binding to Bak. Two anthraquinone metabolites, emodic acid (4) and its new bromo derivative (5), were also isolated from the crinoid and show remarkable similarity to the phenanthroperylenequinone core, suggesting that these metabolites share the same polyketide biosynthetic pathway.
Subject(s)
Anthraquinones/isolation & purification , Anthraquinones/pharmacology , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Echinodermata/chemistry , Animals , Anthraquinones/chemistry , Antineoplastic Agents/chemistry , Candida albicans/drug effects , Drug Screening Assays, Antitumor , Histone Deacetylase 1/antagonists & inhibitors , Humans , Inhibitory Concentration 50 , Macrolides/metabolism , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effectsABSTRACT
The overexpression of the Mcl-1 protein in cancerous cells results in the sequestering of Bak, a key component in the regulation of normal cell apoptosis. Our investigation of the ability of marine-derived small-molecule natural products to inhibit this protein-protein interaction led to the isolation of several bioactive oxy-polyhalogenated diphenyl ethers. A semipure extract, previously obtained from Dysidea (Lamellodysidea) herbacea and preserved in our repository, along with an untouched Dysidea granulosa marine sponge afforded 13 distinct oxy-polyhalogenated diphenyl ethers. Among these isolates were four new compounds, 5, 6, 10, and 12. The structure elucidation of these molecules was complicated by the plethora of structural variants that exist in the literature. During dereplication, we established a systematic method for analyzing this class of compounds. The strategy is governed by trends in the (1)H and (13)C NMR shifts of the aromatic rings, and the success of the strategy was checked by X-ray crystal structure analysis.