ABSTRACT
Benzoquinone ansamycins are important leads for the discovery of novel inhibitors of heat shock protein 90 (Hsp90), a promising target of cancer chemotherapeutics. Intrinsic hepatotoxicity caused by the benzoquinone moiety appeared to be a serious limitation to the development of these compounds. To solve this problem by rational structure optimization, a short series of C18-deoxy analogues of herbimycin A were designed based on putative interactions between the compound and the protein. Chemical synthesis of the target molecules were attempted by following the established synthetic route to the natural product, but resulted in the isolation of four serendipitous C15 phenylated final products. In vitro antiproliferative activity and Hsp90 binding affinity of the compounds were determined, suggesting the C18-oxygen of herbimycin A is removable and bulky lipophilic groups can be accommodated at C15 without loss of activity.
Subject(s)
Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , HSP90 Heat-Shock Proteins/metabolism , Rifabutin/analogs & derivatives , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Inhibitory Concentration 50 , Models, Molecular , Protein Binding , Rifabutin/chemical synthesis , Rifabutin/chemistry , Rifabutin/metabolism , Rifabutin/pharmacologyABSTRACT
Kendomycin, an ansamycin-type natural product first reported in 1996, possesses a series of attractive bioactivities and a unique all-carbon macrocyclic skeleton. To the date, seven total syntheses, two formal total syntheses and a number of synthetic studies on this hot molecule have been reported. In this short review article, we mainly survey and comment on these efforts regarding the difficult macrocyclization strategies.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Lactams, Macrocyclic/chemical synthesis , Rifabutin/analogs & derivatives , Humans , Rifabutin/chemical synthesis , Streptomyces/metabolism , Structure-Activity RelationshipABSTRACT
Genome mining is a rational approach to discovering new natural products. The genome sequence analysis of Streptomyces sp. LZ35 revealed the presence of a putative ansamycin gene cluster (nam). Constitutive overexpression of the pathway-specific transcriptional regulatory gene nam1 successfully activated the nam gene cluster, and three novel naphthalenic octaketide ansamycins were discovered with unprecedented n-pentylmalonyl-CoA or n-butylmalonyl-CoA extender units. This study represents the first example of discovering novel ansamycin scaffolds via activation of a cryptic gene cluster.
Subject(s)
Biological Products/chemical synthesis , Rifabutin/chemical synthesis , Streptomyces/genetics , Biological Products/chemistry , Biological Products/pharmacology , Molecular Structure , Multigene Family , Rifabutin/chemistry , Rifabutin/pharmacologyABSTRACT
The conversion from triene- to diene-typed ansamycins is clarified step by step in Streptomyces seoulensis IFB-A01. Such an intertype convertibility is adopted to establish for the first time the simultaneous mutasynthesis of both types of C17-benzene ansamycins (C17BAs). Three of the newly generated unnatural compounds showed potent cytotoxicity.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Rifabutin/analogs & derivatives , Rifabutin/chemical synthesis , Streptomyces/chemistry , Antineoplastic Agents/chemistry , Drug Screening Assays, Antitumor , Hep G2 Cells , Humans , Lactams, Macrocyclic/chemistry , MCF-7 Cells , Molecular Structure , Rifabutin/chemistry , Rifabutin/pharmacologyABSTRACT
Ansa compounds are gifts from microbes with intriguing molecular structures and highly potent bioactivities. One of the ansa compounds, kendomycin, has an oxa-metacyclophane skeleton with a quinone methide core and a fully substituted tetrahydropyran ring. Beyond a common synthetic strategy for construction of the ansa skeleton (i.e., elongation of an alkyl chain from an aromatic core followed by macrocyclization), we challenged a new method for construction of the ansa skeleton via simultaneous macrocyclization and benzannulation (using an intramolecular Dötz benzannulation). Understanding the reactivity of various Fischer-type ω-alkynyloxy chromium carbene complexes with kendomycin analogue syntheses led to achievement of the total synthesis of kendomycin. Investigations of structure-activity relationships revealed the need for an ansa skeleton for antimicrobial activity. Therefore, we envisage that this intramolecular Dötz benzannulation will enable divergent syntheses of ansa compounds which have important bioactive potential.
Subject(s)
Macrocyclic Compounds/chemical synthesis , Quinones/chemistry , Rifabutin/analogs & derivatives , Coordination Complexes/chemistry , Macrocyclic Compounds/chemistry , Methane/analogs & derivatives , Methane/chemistry , Rifabutin/chemical synthesis , Rifabutin/chemistry , Structure-Activity RelationshipABSTRACT
Benzoquinone ansamycin antibiotic herbimycin A was synthesized in 19 linear steps and 4.2% yield. Highlighted is the design of a chiral γ-lactone as the C11-C15 synthon that enabled a facile catalytic asymmetric synthesis of the challenging C8-C20 fragment of the target molecule. The easy access to the stereogenic centers and high overall yield made the strategy applicable in the molecular editing of benzoquinone ansamycins.
Subject(s)
Benzoquinones/chemistry , Lactones/chemistry , Rifabutin/analogs & derivatives , Anti-Bacterial Agents/chemical synthesis , Catalysis , Lactams, Macrocyclic/chemical synthesis , Molecular Structure , Rifabutin/chemical synthesis , Rifabutin/chemistry , StereoisomerismABSTRACT
The synthesis of a new ansamycin macrolactam derivative that contains an ansa chain based on ansamitocin and an aromatic core related to geldanamycin is reported. The selective introduction of the cyclic carbamoyl group at C7 and C9 relies on a biotransformation using a mutant strain of S. hygroscopicus, the geldanamycin producer. The ansamycin hybrid forms atropisomers that differ in their antiproliferative activity toward cancer cells.
Subject(s)
Antibiotics, Antineoplastic/chemical synthesis , Benzoquinones/chemistry , Lactams, Macrocyclic/chemistry , Rifabutin/chemical synthesis , Streptomyces/chemistry , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/metabolism , Cell Line, Tumor , Humans , Molecular Structure , Rifabutin/chemistry , Rifabutin/metabolism , Streptomyces/metabolismABSTRACT
In an attempt to study the ability of the latest generation of alkyne metathesis catalysts to process sterically hindered substrates, two different routes to the bacterial metabolite kendomycin (1) were explored. Whereas the cyclization of the overcrowded arylalkyne 39 and related substrates turned out to be impractical or even impossible, ring closure of the slightly relaxed diyne 45 was achieved in excellent yield under notably mild conditions with the aid of the molybdenum alkylidyne 2 endowed with triphenylsilanolate ligands. The resulting cycloalkyne 46 was engaged into a gold-catalyzed hydroalkoxylation, which led to benzofuran 47 that had already previously served as a late-stage intermediate en route to 1.
Subject(s)
Alkynes/chemistry , Gold/chemistry , Rifabutin/analogs & derivatives , Catalysis , Cyclization , Molybdenum/chemistry , Polyketides/chemical synthesis , Polyketides/chemistry , Rifabutin/chemical synthesis , Rifabutin/chemistryABSTRACT
A highly stereocontrolled, convergent total synthesis of kendomycin [(-)-TAN2162], an ansa-macrocyclic antibiotic, is reported. The key of the strategy is an unprecedented Tsuji-Trost macrocyclic etherification, followed by a transannular Claisen rearrangement to construct the 18-membered carbocyclic framework. The oxa-six- and five-membered rings were also stereoselectively constructed respectively by a cascade oxidative cyclization at an unfunctionalized benzylic position and using a one-pot epoxidation/5-exo-tet epoxide opening.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Ethers/chemistry , Rifabutin/analogs & derivatives , Molecular Structure , Oxidation-Reduction , Rifabutin/chemical synthesis , Rifabutin/chemistry , StereoisomerismSubject(s)
Benzoquinones/chemistry , Lactams, Macrocyclic/chemical synthesis , Rifabutin/chemistry , Shikimic Acid/chemistry , Binding Sites , Cell Survival/drug effects , Crystallography, X-Ray , HSP90 Heat-Shock Proteins/chemistry , HSP90 Heat-Shock Proteins/metabolism , HeLa Cells , Humans , Lactams, Macrocyclic/chemistry , Lactams, Macrocyclic/toxicity , MCF-7 Cells , Membrane Glycoproteins/chemistry , Membrane Glycoproteins/metabolism , Molecular Docking Simulation , Protein Structure, Tertiary , Rifabutin/chemical synthesis , Rifabutin/toxicity , StereoisomerismABSTRACT
Prins-type macrocyclizations have recently emerged as a successful strategy in the synthesis of polyketide-derived natural products. This reaction provides a concise and selective means to form tetrahydropyran-containing macrocyclic rings of varying size. A high degree of functionality within the macrocycle is tolerated and the yields for these transformations are typically good to excellent. Since the initial report of a Prins macrocyclization reaction in 1979, examples of this approach did not re-emerge until 2008. However, the use of this method in natural product synthesis has rapidly gained momentum in the synthetic community, with multiple examples of this macrocyclization tactic reported in the recent literature.
Subject(s)
Biological Products/chemical synthesis , Biological Products/chemistry , Bryostatins/chemical synthesis , Bryostatins/chemistry , Cyclization , Disaccharides/chemical synthesis , Disaccharides/chemistry , Macrocyclic Compounds/chemistry , Macrolides/chemical synthesis , Macrolides/chemistry , Pyrans/chemistry , Rifabutin/analogs & derivatives , Rifabutin/chemical synthesis , Rifabutin/chemistry , StereoisomerismABSTRACT
Kendomycin is a novel polyketide having a unique quinone methide ansa structure and an impressive biological profile. Herein we provide a chronological overview of the synthetic work towards the title compound. Thus far, over a period of about eight years, eight groups worldwide have published on their synthetic efforts resulting in five total syntheses, one formal synthesis, and a number of fragment syntheses. Most approaches roughly mimic the biogenetic pathway, starting with an aromatic polyphenol subunit to which a polyketide chain is attached. Subsequent key steps include macrocyclization and the formation of the densely substituted tetrahydropyran ring, and then a late-stage oxidation and lactol formation.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Rifabutin/analogs & derivatives , Anti-Bacterial Agents/chemistry , Cyclization , Oxidation-Reduction , Rifabutin/chemical synthesis , Rifabutin/chemistryABSTRACT
One-step formation of the ansa-skeleton realized the synthesis of kendomycin, an ansa-type quinone methide. The Fischer carbene complex derived from the ansa-chain portion was subjected to the intramolecular Dotz benzannulation to afford the desired oxametacyclophane with exclusive regioselectivity. Subsequent Claisen rearrangement, ortho oxidation of the resulting phenol derivative, and mild transformation from p-quinone to p-quinone methide on a silica gel plate furnished kendomycin.
Subject(s)
Rifabutin/analogs & derivatives , Chromium/chemistry , Methane/analogs & derivatives , Methane/chemistry , Rifabutin/chemical synthesis , Rifabutin/chemistry , Spectrophotometry, UltravioletABSTRACT
Two convergent total syntheses of the ansa-polyketide (-)-kendomycin (1) are described. The syntheses benefit from the use of readily available and cheap starting materials. Highly complex diastereoselective Claisen-Ireland rearrangements were used to introduce the (E)-double bond and the C16-Me group. The ring closure of the strained ansa macrocycle was achieved by ring-closing metathesis and a highly efficient combination of macrolactonization and photo-Fries reaction. A protecting group free endgame via an unstable o-quinone is presented. Additionally some unsuccessful synthetic efforts towards the total synthesis of 1 are described.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Rifabutin/analogs & derivatives , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/economics , Anti-Bacterial Agents/pharmacology , Cyclization , Molecular Structure , Oxidation-Reduction , Rifabutin/chemical synthesis , Rifabutin/chemistry , Rifabutin/economics , Rifabutin/pharmacology , StereoisomerismABSTRACT
Efficient synthesis of the fragment C9-C16 bearing the anti,syn stereotriad of ansamycin antibiotics is described. Key steps for controlling the configuration of the three stereogenic centers involve a stereoselective Reformatsky-type reaction followed by a diastereoselective reduction of a beta-ketosulfoxide.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Polymers/chemical synthesis , Rifabutin , Anti-Bacterial Agents/chemistry , Catalysis , Molecular Structure , Polymers/chemistry , Rifabutin/analogs & derivatives , Rifabutin/chemical synthesis , Rifabutin/chemistry , StereoisomerismSubject(s)
Anti-Bacterial Agents/chemical synthesis , Rifabutin/analogs & derivatives , Aldehydes/chemical synthesis , Aldehydes/chemistry , Anti-Bacterial Agents/chemistry , Benzofurans/chemical synthesis , Benzofurans/chemistry , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Cyclization , Rifabutin/chemical synthesis , Rifabutin/chemistryABSTRACT
The kendomycin skeleton was prepared by a highly convergent strategy in which the benzofuran fragment and the acyclic iodide fragment were prepared by standard methods and joined using a Suzuki coupling. The distinctive reaction in our approach was an intramolecular Prins cyclization that assembles the macrocyclic ring in good yield. Modeling studies demonstrate that the acyclic chain is predisposed for macrocycle formation. Ultimately, the product was correlated with one of Lee's advanced intermediates for a formal total synthesis of kendomycin.
Subject(s)
Rifabutin/analogs & derivatives , Cyclization , Macrocyclic Compounds/chemical synthesis , Rifabutin/chemical synthesis , StereoisomerismABSTRACT
An enantioselective synthesis of (-)-kendomycin is described and is based on the application of the organosilane-based [4 + 2]-annulation strategy for the assembly of the C1a-C10 fragment. An underutilized samarium(II) iodide-assisted cyclization (intramolecular Barbier-type reaction) is employed to afford the protected macrocycle.
Subject(s)
Rifabutin/analogs & derivatives , Cyclization , Iodides/chemistry , Rifabutin/chemical synthesis , Samarium/chemistry , StereoisomerismABSTRACT
A novel series of spirorifamycins was synthesized and their antibacterial activity evaluated both in vitro and in vivo. This new series of rifamycins shows excellent activity against Staphylococcus aureus that is equivalent to rifabutin. However, some compounds of the series exhibit lower MICs than rifabutin against rifampin-resistant strains of S. aureus. Further, compound 2e exhibits comparable efficacy in vivo in a murine model of S. aureus septicemia model following administration by either oral or parenteral dosing routes.
Subject(s)
Rifabutin/chemical synthesis , Rifabutin/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Drug Administration Routes , Mice , Microbial Sensitivity Tests , Rifamycins/chemical synthesis , Rifamycins/pharmacology , Sepsis/drug therapy , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
The synthesis, structure, and biological evaluation of a series of novel rifamycin derivatives, Rifastures (RFA) with potent anti-tuberculosis activity are presented. Some of these derivatives showed higher in vitro activity than rifabutin and rifampicin against not only Mycobacterium tuberculosis strains but also against MAC and Mycobacterium kansasii.