Novel Naphthoquinones from a Streptomyces sp.

Abstract

Cdc25A assay-guided fractionation of a fermentation broth derived from a Streptomyces sp. resulted in the isolation of four novel naphthoquinones 1~4. Structures of these compounds were deduced by NMRand mass spectrometry. Two of them, 3 and 4, incorporate a modified cysteine residue which is observed for the first time in this class of natural products. Naphthoquinones 1~4 showed weak activity against cdc25A phosphatase.Cyclin/cdk (cyclin-dependent kinase) complexes serve as regulatory checkpoints for cell cycle progression.1}Cell cycle progression is delayed when the activities of cdks are suppressed through phosphorylation of their critical threonine and tyrosine residues. Cdc25, a family of dual specificity phosphatases, activate cdks by dephosphorylation of threonine and tyrosine residues and thus play a significant role in cell cycle progression.Cdc25Ais a memberof this family of phosphatases that appears to function early in the cell cycle.2) Furthermore, it has been shown that abnormal expression of cdc25A in the presence of RASmutants or RBdeletion mutants can lead to oncogenic transformation.3'4) Therefore, cdc25Aappears to be an attractive target for the discovery of novel cancer therapeutic agents. During the screening of microbial fermentations for cdc25A phosphatase inhibitors, an extract derived from a Streptomyces sp. was discovered to be active. Weherein report the production, purification, structure determination and cdc25A phosphatase activity of four novel napthoquinones. Experimental General MethodsHPLCseparations were performed on Rainin SD-1 and HPXLsystems with an UV-1absorbance detector (/l=240nm) using Dynamax 60A Microsorb phenyl (41.4 x 250mm, flow rate 45ml/minute) and Dynamax 60A C18 (21.4x250mm, flow rate 12ml/minute) column.UV absorption spectra were measured as the compounds eluted in 0.5% NH4OAc-CH3CN gradient using a Waters 717 system equipped with a Waters 996 photodiode array detector. IR spectra were determined on a Nicolet 510 P spectrophotometer. Optical rotations were measured on a JASCOmodel DIP-70 polarimeter.FAB-MS and HRFAB-MS were obtained on a VG Analytical ZAB-2-SE mass spectrometer. NMRspectra were determined on a Varian Unity (1H: 500MHz; 13C: 125.7MHz) spectrometer using a Z-SPEC microdual microsampleprobe. Carbon multiplicities were assigned by DEPTexperiments. Standard pulse sequences were employed for all 2D NMRexperiments. FermentationThe producing organism was isolated from a soil sample collected in Curacao. Stock cultures were kept as a suspension in 10%glycerol-5%lactose in the vapor phase of liquid nitrogen. Thawed aliquots (1 ml each)were inoculated into 3x50ml portions of medium containing 3% Trypticase Soy Broth (BBL), 0.5% glucose, 0.4% maltose, 0.3% yeast extract, and 0.2%MgSO4à"7H2O in de-ionized water. Each portion of inoculated mediumwas contained in a 250 ml Erlenmeyer flask and was incubated at 250rpm for 48 hours at 30°C

Antibacterial Salinaphthoquinones from a Strain of the Bacterium Salinispora arenicola Recovered from the Marine Sediments of St. Peter and St. Paul Archipelago, Brazil

“…Despite the large number of rifamycins reported, either natural or synthetic, the amino group is mostly found at the C-2 position of the naphthoquinone nucleus. Naturally occurring 3-aminonaphthoquinones, although rare, have been reported previously. , This can explain the presence, in this case, of compound 3 (3-amino) among compounds 1 , 2 , 4 , and 5 .…”

“…In conclusion, compounds 1 – 5 are 2- or 3-amino-1,4-naphthoquinones; however, they have the important core present in several biologically important natural products such as rifamycins, salinisporamycin, and a Cdc25A inhibitor …”

Amaryllidaceae, Sceletium, imidazole, oxazole, thiazole, peptide and miscellaneous alkaloids

“…The first is 524, the second 525 then 526 and its epimer. 182 A patent 183 describes a product of the micro-organism Streptomyces melanovinaceus as being antitumourous. Designated DX-512-1 it was found to be a mixture of products whose structure incorporates 527.…”

Discovery of Mycothiogranaticins from Streptomyces vietnamensis GIMV4.0001 and the Regulatory Effect of Mycothiol on the Granaticin Biosynthesis

“…Sulfur incorporation can significantly expand the structural diversity and bioactivities of many naturally occurring molecules ( Hai et al, 2021 ), many sulfur-containing natural products, such as penicillin and ixabepilone, have been approved for clinic therapy. However, bacterial sulfur-containing aromatic polyketides are relatively rare, with only a few examples reported over the past decades ( Etoh et al, 1987 ; Ohta et al, 1987 ; Rohr and Zeeck, 1987 ; Miyata et al, 1992 ; Aoyama et al, 1993 ; Carney et al, 1997 ; Kulanthaivel et al, 1999 ; Sasaki et al, 2010 ; Taguchi et al, 2013 ; Wang et al, 2013 ; Woo et al, 2013 ; Taguchi et al, 2015 ; Bilyk et al, 2016 ; Che et al, 2016 ; Xie et al, 2016 ; Nakashima et al, 2017 ; Matsuo et al, 2019a ; Bae et al, 2019 ; Matsuo et al, 2019b ; He et al, 2019 ; Fang et al, 2020 ; Cao et al, 2021 ). Amongst these reports, naquihexcin A could inhibit the proliferation of the adriamycin resistant human breast cancer ( Che et al, 2016 ); nanaomycin K showed an inhibitory effect on the epithelial-mesenchymal transition ( Matsuo et al, 2019a ); and naquihexcin E exhibited a notable anti-HIV activity ( He et al, 2019 ).…”