Combinatorial metabolic engineering of Streptomyces sp. CB03234-S for the enhanced production of anthraquinone-fused enediyne tiancimycins.

Background: Anthraquinone-fused enediynes (AFEs) are excellent payloads for antibody-drug conjugates (ADCs). The yields of AFEs in the original bacterial hosts are extremely low. Multiple traditional methods had been adopted to enhance the production of the AFEs.

Anti-HER2 Immunoliposomes: Antitumor Efficacy Attributable to Targeted Delivery of Anthraquinone-Fused Enediyne.

Although natural products are essential sources of small-molecule antitumor drugs, some can exert substantial toxicities, limiting their clinical utility. Anthraquinone-fused enediyne natural products are remarkably potent antitumor drug candidates, and uncialamycin and tiancimycin (TNM) A are under development as antibody-drug conjugates. Herein, a novel drug delivery system is introduced for TNM A using anti-human epidermal growth factor receptor 2 (HER2) immunoliposomes (ILs).

Morphing Natural Product Platensimycin via Heck, Sonogashira, and One-Pot Sonogashira/Cycloaddition Reactions to Produce Antibiotics with In Vivo Activity.

Type II fatty acid synthases are promising drug targets against major bacterial pathogens. Platensimycin (PTM) is a potent inhibitor against -ketoacyl-[acyl carrier protein] synthase II (FabF) and -ketoacyl-[acyl carrier protein] synthase I (FabB), while the poor pharmacokinetics has prevented its further development. In this work, thirty-two PTM derivatives were rapidly prepared via Heck, Sonogashira, and one-pot Sonogashira/cycloaddition cascade reactions based on the Gram-scale synthesis of 6-iodo PTM ().

Discovery of a DNA Topoisomerase I Inhibitor Huanglongmycin N and Its Congeners from sp. CB09001.

Huanglongmycin (HLM) congeners G-N (-) were isolated from sp. CB09001. Among them, - possesses a tricyclic scaffold with benzene-fused pyran/pyrone, confirmed by X-ray single crystal diffraction analysis of .

Synthesis and biological evaluation of platensic alcohol as an adamantane surrogate in antitumor drug lead adaphostin.

Adamantane has been widely used as a "lipophilic bullet" in drug discovery and development, due to its unique diamond-like architecture with benign pharmacological/ pharmaceutical properties. Platensimycin is a natural product isolated from a soil streptomycete, which contains an adamantane-like moiety extensively modified from a diterpenoid precursor. In the current study, platensic alcohol was semisynthesized from platensimycin and used as an adamantane surrogate in anticancer drug lead adaphostin.

Semisynthesis and Biological Evaluation of Platencin Thioether Derivatives: Dual FabF and FabH Inhibitors against MRSA.

The discovery and clinical use of multitarget monotherapeutic antibiotics is regarded as a promising approach to reduce the development of antibiotic resistance. Platencin (PTN), a potent natural antibiotic initially isolated from a soil actinomycete, targets both FabH and FabF, the initiation and elongation condensing enzymes for bacterial fatty acid biosynthesis. However, its further clinical development has been hampered by poor pharmacokinetics.

Yangpumicins F and G, Enediyne Congeners from DSM 45577.

Enediyne natural products are among the most cytotoxic small molecules and thus excellent payload candidates for the development of antibody-drug conjugates (ADCs). Here we report the isolation and structural elucidation of two new 10-membered anthraquinone-fused enediynes, yangpumicins (YPM) F () and G (), together with five known congeners, YPM A-E (-), from DSM 45577. YPM F () and G () showed strong cytotoxicity against the tested human cancer cell lines, as well as activity against several Gram-positive and Gram-negative pathogens.

Late-Stage Functionalization of Platensimycin Leading to Multiple Analogues with Improved Antibacterial Activity in Vitro and in Vivo.

Bacterial fatty acid synthases are promising antibacterial targets against multidrug-resistant pathogens. Platensimycin (PTM) is a potent FabB/FabF inhibitor, while its poor pharmacokinetics hampers the clinical development. In this study, a focused library of PTM derivatives was prepared through thiolysis of PTM oxirane (), followed by various C-C cross-coupling reactions in high yields.

Syn-2, 3-diols and anti-inflammatory indole derivatives from sp. CB09001.

Two new natural diols, (2S, 3S, 4S)-4-methyl-1-phenylhexane-2,3-diol () and (2S, 3S)-4-methyl-1-phenylpentane-2,3-diol (), together with five known compounds, xenocyloins B-D (), lumichrome () and thymidine () were isolated from sp. CB09001. The absolute configurations of and established by crystallographic structure analysis.

Stereoselective functionalization of platensimycin and platencin by sulfa-Michael/aldol reactions.

Bioinspired sulfa-Michael/aldol cascade reactions have been developed for the semisynthesis of sulfur-containing heterocyclic derivatives of platensimycin and platencin, with three newly formed contiguous stereogenic centers. Density functional theory calculations revealed the mechanism for the stereochemistry control. This method was used in a synthesis of a platensimycin thiophene analogue with potent antibacterial activities against Staphylococcus aureus.

Semisynthesis of Platensimycin Derivatives with Antibiotic Activities in Mice via Suzuki-Miyaura Cross-Coupling Reactions.

Platensimycin (PTM), originally isolated from soil bacteria Streptomyces platensis, is a potent FabF inhibitor against many Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. However, the further clinical development of PTM is hampered by its poor pharmacokinetic properties. In this study, 20 PTM derivatives were prepared by Suzuki-Miyaura cross-coupling reactions catalyzed by Pd (0)/C.

Biomimetic Stereoselective Sulfa-Michael Addition Leads to Platensimycin and Platencin Sulfur Analogues against Methicillin-Resistant Staphylococcus aureus.

Several sulfur-containing platensimycin (PTM) and platencin (PTN) analogues, with activities comparable to the parent natural products, have recently been discovered from microorganisms, implying a biomimetic route to diversify the PTM and PTN scaffolds for structure-activity relationship study. We present here a substrate-directed and scaleable semisynthetic strategy to make PTM and PTN sulfur analogues with excellent diasteroselectivity, without using any chiral catalysts. Most of the sulfur analogues showed strong activities against clinical Staphylococcus aureus isolates, with minimum inhibitory concentrations of 0.

A nordehydroabietyl amide-containing chiral diene for rhodium-catalysed asymmetric arylation to nitroolefins.

A highly enantioselective rhodium catalysed asymmetric arylation (RCAA) of nitroolefins with arylboronic acids is presented using a newly developed, C-symmetric, non-covalent interacted, phellandrene derived, nordehydroabietyl amide-containing chiral diene under mild conditions. Stereoelectronic effects were studied, suggesting an activation of the bound substrate through the secondary amide as a hydrogen-bond donor.