From an actinomycete strain, Streptomyces sp. K99-5041, lanopylins A1, B1, A2 and B2 were isolated as new natural products that inhibited the reaction of recombinant human lanosterol synthase. The crude extract from the whole broth of this strain was fractionated by silica gel column chromatography to afford an active fraction that showed a single spot on TLC. Detailed analyses of this fraction with liquid chromatography-atmospheric pressure chemical ionization mass spectrometry revealed that it contained 20 homologous compounds with differing side chain lengths. The fraction was separated by preparative HPLC to afford four of these homologues, lanopylins A1, B1, A2 and B2. Detailed spectroscopic analyses of these isolated compounds led to the identification of their structures. Lanopylins A1 and B1 were (3E)-isohexadecylmethylidene-2-methyl-1-pyrroline and (3E)-hexadecylmethylidene-2-methyl-1-pyrroline, respectively, and lanopylins A2 and B2 were homologues with the insertion of one cis-ethylenylidene in the side chain of lanopylins A1 and B1, respectively. These compounds inhibited recombinant human lanosterol synthase with IC50 values of 15, 18, 33, and 41μM, respectively.
New antibiotic compounds, named cyrmenins, were isolated from the culture broth of strains of the myxobacteria Cystobacter armeniaca and Archangium gephyra. The compounds belong to the group of β-methoxyacrylate (MOA) inhibitors and are the first naturally occuring nitrogen-linked MOAs. The cyrmenins show nearly the same antifungal activity as strobilurin A, but are less toxic in a growth inhibition assay with L929 mouse cells. Cyrmenins inhibit NADH oxidation by submitochondrial particles from beef heart. Investigations by difference spectroscopy showed that cyrmenin B1 blocks the electron transport within the cytochrome bc1-segment (complex III) of the respiratory chain.
Staplabin and SMTPs, triprenyl phenol metabolites of the fungus Stachybotrys microspora, are a family of non-lysine-analog plasminogen modulators that enhance both activation and fibrin binding of plasminogen by modulating plasminogen conformation. These compounds, including SMTP-4, -5, -6, -7 and -8, have an amino acid or an amino alcohol moiety in their structure, and precursor amine feeding greatly increases the biosynthesis of a metabolite of interest. In the present study, we have isolated five novel SMTPs (designated SMTP-4D, -5D, -6D, -7D and -8D) from precursor D-amino acid-fed cultures. Physico-chemical properties as well as chromatographic behavior were distinct from those of the corresponding L-amino acid analogs, which are selectively accumulated in L-amino acid-fed cultures and share common properties with corresponding natural products. The D-series SMTPs enhanced urokinase-catalyzed plasminogen activation by 10-fold at 80-180μM.
Thirty five oxapenem analogues substituted with a range of tertiary groups at C-2 have been synthesised and evaluated as broad-spectrum β-lactamase inhibitors. All analogues enhanced the activity of ceftazidime against bacterial isolates producing Class A and Class C β-lactamases. Compounds with cyclic substituents at C-1' (attached to C-6) were associated with enhanced antibacterial activity against Staphylococcus aureus. (R) Stereochemistry at C-1' led to synergistic activity against β-lactamase negative enterococci. (S) Stereochemistry at C-1' was associated with enhanced inhibition of Class A β-lactamases and lack of synergistic activity against enterococci. AM-113 was unstable in serum and not detectable following subcutaneous or oral dosing in mice. AM-112 and AM-115 achieved good serum levels following subcutaneous dosing. AM-114 exhibited 30% bioavailability following oral dosing. AM-112 [(1'R, 5R, 6R)-2-(4-ammonio-1, 1-dimethylbutyl)-6-(1'-hydroxyethyl)oxapenem-3-carboxylate] achieved the greatest protection of ceftazidime against Gram-negatives producing Class A or C β-lactamases.
Milbemycin α17, a 14-demethyl congener of milbemycin A4, has been reported as a natural product. In this paper, we report the successful development of a chemical derivation method to synthesize milbemycin α17 from milbemycin A4, as well as our use of a similar method to prepare 24-demethylmilbemycin A4 from the same precursor. The acaricidal activities of these compounds were assessed against the organophosphorus-sensitive two-spotted spider mites (Tetranychus urticae) on the primary leaves of cowpea plants (Vigna sinesis Savi species) by spraying.