ABSTRACT
Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition ( Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.
Subject(s)
Cyclophilins/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacokinetics , Administration, Oral , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Biological Availability , Cell Line , Cyclophilins/chemistry , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Hepacivirus/drug effects , Lactones/administration & dosage , Lactones/chemistry , Lactones/pharmacokinetics , Lactones/pharmacology , Models, Molecular , Protein Conformation , Spiro Compounds/administration & dosage , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacologyABSTRACT
Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18-C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a π-stacking interaction with Arg55 of cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold to generate new lead compounds in the search for orally bioavailable cyclophilin inhibitors.
Subject(s)
Cyclophilins/antagonists & inhibitors , Cells, Cultured , Chromatography, Liquid , Crystallography, X-Ray , Drug Discovery , Humans , Hydrogen Bonding , Lactones/chemistry , Lactones/pharmacology , Proton Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray Ionization , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship , Surface Plasmon Resonance , ThermodynamicsABSTRACT
By employing a diverted total synthesis strategy with late-stage intermediates, 10,11-dihydrodictyostatin ( 5) was prepared and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including the NCI/ADR Taxol-resistant cell line. This novel dictyostatin analogue was found to retain potent antimitotic activity, with a comparable profile to discodermolide and Taxol, functioning by microtubule stabilization and G2/M arrest. These SAR studies provide further insight into the interaction between dictyostatin ( 1) and its tubulin target.
Subject(s)
Antineoplastic Agents , Macrolides/chemistry , Macrolides/chemical synthesis , Macrolides/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Humans , Molecular Conformation , Molecular Structure , Paclitaxel/pharmacology , Porifera/chemistry , Stereoisomerism , Tubulin/metabolismABSTRACT
Novel analogues of the microtubule-stabilising agent dictyostatin were designed using existing SAR information from the structurally related discodermolide, synthesised by a late-stage diversification strategy and evaluated in vitro for growth inhibition against a range of human cancer cell lines, including those known to exhibit Taxol-resistance (AsPC-1, DLD-1, PANC-1, NCI/ADR).
Subject(s)
Drug Resistance, Neoplasm , Macrolides/chemical synthesis , Antineoplastic Agents, Phytogenic , Cell Line, Tumor , Chemistry, Pharmaceutical/methods , Drug Design , Drug Screening Assays, Antitumor , Humans , Macrolides/chemistry , Macrolides/pharmacology , Models, Chemical , Molecular Conformation , Paclitaxel/chemistry , Paclitaxel/pharmacology , Structure-Activity RelationshipABSTRACT
The first enantioselective total synthesis of (+)-phakellstatin and (+)-dibromophakellstatin was achieved. Key steps in the synthesis were a desymmetrization of the diketopiperazine (S,S)-cyclo (Pro, Pro) via a diastereoselective acylation, an intramolecular Mitsunobu reaction to introduce the C6 aminal, and a tandem Hofmann rearrangement/cyclization to simultaneously introduce the C10 quaternary aminal center and deliver the cyclic urea. The synthesis also demonstrates the unusual stability of pyrrolo aminals. Importantly, this strategy has the potential for producing phakellstatin derivatives, derived from (R,R)-cyclo (Pro, Pro), necessary for biological studies. A similar annulation protocol is also expected to be applicable to the synthesis of palau'amine.
Subject(s)
Imidazoles/chemical synthesis , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Imidazoles/pharmacology , Porifera/chemistry , StereoisomerismABSTRACT
[reaction: see text] Monoenolates of C(2)-symmetric, proline-derived piperazine-2,5-diones were generated and trapped with a variety of electrophiles to produce, in a highly diastereoselective fashion, functionalized diketopiperazines (DKPs). These reactions provide the basis for an asymmetric, desymmetrization strategy toward the marine alkaloids phakellstatin and phakellin. The relative stereochemistry of the functionalized DKPs was confirmed by single-crystal X-ray analysis and/or NOE experiments. Bis-functionalization of the DKPs was also found to proceed with high levels of diastereoselectivity.