ABSTRACT
Perphosphorylated pentopyranoses and pentofuranoses were synthesized from parent carbohydrates as potential allosteric effectors of hemoglobin (Hb). The construction of seven- and eight-membered cyclic pyrophosphates was also carried out successfully on most of the pentoses. All final compounds were tested for their efficiency on oxygen release from human Hb. Most proved to be efficient allosteric effectors, some of them with an affinity toward Hb and an effect on oxygen release from Hb approaching that of myo-inositol hexakisphosphate, which is one of the most active allosteric effectors of Hb. The efficacy was higher for free phosphates than for pyrophosphates.
Subject(s)
Diphosphates/chemistry , Hemoglobins/chemistry , Oxygen/metabolism , Pentoses/chemistry , Polyphosphates/chemistry , Allosteric Regulation , Diphosphates/chemical synthesis , Diphosphates/pharmacology , Hemoglobins/metabolism , Humans , Polyphosphates/chemical synthesis , Polyphosphates/pharmacology , Protein Binding , Structure-Activity RelationshipABSTRACT
Hypothemycin and related resorcylic acid lactones (RAL) bearing a cis-enone moiety have emerged as an alternative pharmacophore to heterocyclic motifs for kinase inhibition, and are endowed with a unique selectivity filter based on the irreversible reaction with a subset of the kinome bearing a suitably positioned cysteine residue. Two prototypical examples of "edited" RAL were evaluated for antitumoral, antimetastatic and antiangiogenic efficacy in an orthotopic murine renal cell carcinoma (RENCA) model. Both compounds (3 and 5) are good inhibitors of VEGFRs in vitro, and inhibited tumor growth in vivo with comparable efficacy to sunitinib, an FDA-approved VEGFRs inhibitor. Compound 3 promoted lung metastasis to a similar extent as sunitinib, while compound 5 strongly inhibited lung metastasis. This study attests to the potential of irreversible kinase inhibitors and molecular editing of natural pharmacophores and provides encouraging results to a clinically significant problem.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Lactones/pharmacology , Protein Kinase Inhibitors/pharmacology , Angiogenesis Inhibitors/chemical synthesis , Animals , Carcinoma, Renal Cell/blood supply , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Cell Growth Processes/drug effects , Cell Line, Tumor , Female , Inhibitory Concentration 50 , Kidney Neoplasms/blood supply , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Lactones/chemical synthesis , Mice , Mice, Inbred BALB C , Protein Kinase Inhibitors/chemical synthesis , Random Allocation , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Receptor, Platelet-Derived Growth Factor beta/metabolism , Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-1/metabolism , Xenograft Model Antitumor AssaysSubject(s)
Fluorine/chemistry , Lactones/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinases/chemistry , Binding Sites , Lactones/chemical synthesis , Lactones/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Proto-Oncogene Proteins c-kit/antagonists & inhibitors , Proto-Oncogene Proteins c-kit/metabolism , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/metabolismABSTRACT
A self-assembled monolayer (SAM) on gold was formed with specifically perdeuterated hexaethylene glycol-terminated alkanethiol HS(CD(2))(12)(O-CH(2)-CH(2))(6)OCH(3) (D-OEG). The structure of the d-alkane and the oligoethylene glycol (OEG) parts of the molecule in a SAM was studied by means of polarization modulation infrared reflection absorption spectroscopy. The D-OEG monolayers are highly ordered and exist in a crystalline phase. The d-alkane chain adopts an all-trans conformation. Both, the d-alkane chain and long axis of the OEG part make an angle of 26.0 degrees +/- 1.5 degrees with respect to the surface normal, a value characteristic for the tilt of solid n-alkane thiols in the SAMs on Au. The positions of nu(as)(COC) and CH(2) wagging and rocking modes indicate a helical arrangement of the OEG chains. The D-OEG SAMs were exposed to 25 muM Br(2) in two ways: (i) by immersion into the Br(2) solution and (ii) in the galvanic cell Au|D-OEG SAM|25 muM Br(2) + 0.1 M Na(2)SO(4)|| 50 muM KBr + 0.1 M Na(2)SO(4)|Au. In the galvanic cell, the oxidant (Br(2)) is scavenged by a heterogeneous electron transfer reaction, slowing the reaction of D-OEG with Br(2). The slow progress of the reaction with Br(2) allowed us to draw conclusions about molecular rearrangements taking place during this reaction. The reaction with Br(2) starts on boundaries and/or defects present in the SAM. First, at the defect place, the alpha-C atom of the OEG chain reacts with Br(2) and the OEG part of the molecule is removed from the monolayer. In consequence an increase in disorder in the OEG part of the SAM is observed. The same mechanism of the reaction with Br(2) is applied for the d-dodecane alkanethiol part of the molecule. This reaction is slow, thus the order and the tilt of the hydrocarbon chain changes only a little during the reaction time.
ABSTRACT
A library of resorcylic acid lactones (RAL) containing a cis-enone moiety targeting kinases bearing a cysteine residue within the ATP-binding pocket was prepared using a fluorous-mixture synthesis and evaluated against a panel of 19 kinases thus providing important structure-activity trends. Two new analogues were then profiled for their selectivity against a panel of 402 kinases providing the broadest evaluation of this pharmacophores' selectivity.
Subject(s)
Fluorine/chemistry , Hydroxybenzoates/chemistry , Lactones/chemical synthesis , Phosphotransferases/metabolism , Protein Kinase Inhibitors/chemical synthesis , Adenosine Triphosphate/chemistry , Lactones/chemistry , Protein Kinase Inhibitors/chemistry , Small Molecule Libraries , Structure-Activity RelationshipABSTRACT
The resorcylic acid lactones (RAL) are endowed with diverse biological activity ranging from transcription factor modulators (zearalenone and zearalenol) to HSP90 inhibitors (radicicol and pochonin D) and reversible (aigialomycin D) as well as irreversible kinase inhibitors (hypothemycin and other RAL containing a cis-enone). Our interest in broadening the diversity of this family beyond naturally occurring diversity has led us to seek a general approach that could be used to address the entire spectrum of functionalities present within this family. Herein, we present our efforts on accessing macrocycles bearing an alkane, alkene, or epoxide at the benzylic position from a common benzylic sulfide intermediate to access L-783277, LL-Z1640-2, and hypothemycin.
Subject(s)
Hydroxybenzoates/chemistry , Lactones/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Resorcinols/chemical synthesis , Alkylation , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/metabolism , Lactones/chemistry , Oxidation-Reduction , Protein Kinase Inhibitors/chemistry , Resorcinols/chemistry , Safrole/analogs & derivatives , Safrole/chemistry , Stereoisomerism , Sulfides/chemistry , Zearalenone/analogs & derivatives , Zearalenone/chemical synthesis , Zearalenone/chemistryABSTRACT
The total synthesis of luminacin D (1) is reported on the basis of two aldol reactions to form the carbohydrate sector, aldehyde 30. Reaction of aldehyde 30 with the aryllithium intermediate derived from aryl iodide 38, cleavage of the silyl ether, and oxidation led to keto aldehyde 41. This advanced intermediate could be converted to luminacin 1 and its 6',8'-epimer.
