ABSTRACT
Introducing a second chiral center on our previously described 1,2,4-triazole, allowed us to increase diversity and elongate the 'C-terminal part' of the molecule. Therefore, we were able to explore mimics of the substance P analogs described as inverse agonists. Some compounds presented affinities in the nanomolar range and potent biological activities, while one exhibited a partial inverse agonist behavior similar to a Substance P analog.
Subject(s)
Receptors, Ghrelin/metabolism , Triazoles/chemistry , Fluorescence Resonance Energy Transfer , Indoles/chemistry , Indoles/pharmacology , Inhibitory Concentration 50 , Ligands , Receptors, Ghrelin/agonists , Structure-Activity Relationship , Substance P/chemistry , Tryptophan/analogs & derivatives , Tryptophan/chemistry , Tryptophan/pharmacologyABSTRACT
Ghrelin receptor ligands based on a trisubstituted 1,2,4-triazole scaffold were recently synthesized and evaluated for their in vitro affinity for the GHS-R1a receptor and their biological activity. In this study, replacement of the α-aminoisobutyryl (Aib) moiety (a common feature present in numerous growth hormone secretagogues described in the literature) by aromatic and heteroaromatic groups was explored. We found potent antagonists incorporating the picolinic moiety in place of the Aib moiety. In an attempt to increase affinity and activity of our lead compound 2, we explored the modulation of the pyridine ring. Herein we report the design and the structure-activity relationships study of these new ghrelin receptor ligands.
Subject(s)
Receptors, Ghrelin/antagonists & inhibitors , Receptors, Ghrelin/metabolism , Triazoles/chemical synthesis , Triazoles/metabolism , Animals , Cell Line , Humans , Mice , Protein Binding/physiology , Structure-Activity Relationship , Triazoles/pharmacologyABSTRACT
A new series of substituted tri-/tetraazabenzo[3,2-a]fluorene-5,6-diones and their corresponding oxime derivatives have been synthesized and spectroscopically characterized. The antiproliferative activities of all compounds were evaluated on at least three different cell lines.
Subject(s)
Antineoplastic Agents/chemical synthesis , Aza Compounds/chemical synthesis , Fluorenes/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Aza Compounds/chemistry , Benzene Derivatives/chemical synthesis , Benzene Derivatives/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Inhibitory Concentration 50 , Molecular StructureABSTRACT
A series of indazolo[4,3-gh]isoquinolinones derivatives have been synthesized to decrease cardiotoxic side effects in comparison to Mitoxantrone. The antiproliferative effects of different side chains were investigated and tested on at least four different cell lines of cervix, ovarian, CNS, NSCLC (non-small-cell lung cancer) and colon carcinoma. In addition to antiproliferative activities, influence on cell cycle and intercalation behavior have been tested.
Subject(s)
Antineoplastic Agents/chemical synthesis , Indazoles/chemistry , Quinolones/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cell Proliferation/drug effects , DNA/chemistry , DNA/metabolism , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Mitoxantrone/chemistry , Mitoxantrone/toxicity , Quinolones/chemical synthesis , Quinolones/toxicity , S Phase Cell Cycle Checkpoints/drug effects , Structure-Activity RelationshipABSTRACT
A series of 6-azanaphthoquinone pyrrolo-annelated derivatives carrying different basic side chains have been synthesized. The antiproliferative activities of all compounds were evaluated on at least four different cell lines with Mitoxantrone as reference compound. Cytotoxic effects and DNA intercalation behavior were investigated.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Naphthoquinones/chemistry , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
A series of azanaphthoquinone pyrrolo-annelated derivatives attached to basic side chains have been synthesized. The antiproliferative activities of all compounds were evaluated on at least four different cell lines. The effects on cell cycle and intercalation were investigated.
Subject(s)
Antineoplastic Agents/pharmacology , Naphthoquinones/pharmacology , Pyrroles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Molecular Structure , Naphthoquinones/chemical synthesis , Naphthoquinones/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Two series of azanaphthoquinone annelated pyrrolo oximes have been synthesized. The antiproliferative activities of 10 compounds were evaluated on at least four different cell lines. One series of pyrrolo derivatives showed high cytotoxic activity. The effects on cell cycle and caspase activity were investigated. Compounds 9a and 9b showed an accumulation of cells in G2/M phase. Substantial and dose-dependent caspase activity was found after treatment of cells with 9a and 9b. This indicates an apoptosis inducing property of these compounds.
Subject(s)
Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Mitoxantrone/chemical synthesis , Naphthoquinones/chemical synthesis , Oximes/chemical synthesis , Pyrroles/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Caspases/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Mitoxantrone/analogs & derivatives , Mitoxantrone/pharmacology , Molecular Structure , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Oximes/chemistry , Oximes/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacologyABSTRACT
1-Phenyl-4-piperazinyl-carbonyl-substituted nitrogen-containing heterocycles were discovered at Zentaris as a new class of potent, synthetic, small molecule tubulin inhibitors with strong antiproliferative activity. The lead structure of this class, D-24203, proved to be a potent inhibitor of in vivo tumor growth in different xenograft models including mammary and renal cancers. As part of our efforts in the lead optimization process to expand structural diversity as well as to optimize bioavailability parameters such as solubility and metabolic stability for these compounds, we produced and evaluated a focused library containing 320 compounds. Five new heterocyclic compound classes with comparable activity properties in the cytotoxicity and tubulin polymerization assay could be identified. In silico calculated bioavailability parameters for selected library members provides new compound classes with improved solubility properties. Library design, development of adequate solution phase methodology, and synthesis will be presented, as well as results of lead optimization.
