Dextrorotatory Chromomycins from the Marine Streptomyces sp. Associated to Palythoa caribaeorum

Abstract

A Streptomyces sp. (BRA-384) was selected among nine strains of bacteria isolated from the zoanthids Palythoa caribaeorum due to the high cytotoxic activity presented by its EtOAc extract (inhibitory concentration mean (IC 50) of 2 ng mL-1) against colon cancer cell line. From the EtOAc extract of BRA-384 three new chemical entities (A 6 , A 7 and A 8) and one dextrorotatory chromomycin (A 5), a promising class of anticancer compounds, were identified. The cytotoxicity of chromomycins A 5 to A 8 was tested against five tumor cell lines (HCT 116 (human colon adenocarcinoma), MCF-7 (human breast carcinoma), PC-3M (human metastatic prostate cancer), 501-mel (human metastatic melanoma) and MM200 (metastatic melanoma)). All chromomycins were highly potent showing IC 50 values from 0.2 to 133 nM. Chromomycin A 5 was consistently the most potent over all tested cells (IC 50 values from 0.2 in MM200 to 7.9 nM in PC-3M), inclusive when compared to the standard chemotherapeutic agent doxorubicin, that presented IC 50 values ranging from 147 to 568 nM against MM200 and MCF-7, respectively.

Antibacterial Activity of Chromomycins from a Marine-Derived Streptomyces microflavus

“…The compounds are distinguished by the type of sugar; chromomycins have a disaccharide chain consisting of two d -olioses at C-2 and a trisaccharide chain consisting of two D-olivoses and L-chromose. Chromomycins possess a broad range of biological activities such as antimicrobial [ 10 , 11 ], anticancer [ 12 , 13 , 14 ], and antiviral [ 15 ] activities, and are found in terrestrial and marine bacteria of the genus Streptomyces . Similar to other aureolic acid family members, chromomycins interact with the DNA helix minor groove in regions with high GC content and in a non-intercalative way with Mg 2+ cations, causing DNA damage in treated cells [ 16 , 17 , 18 ].…”

Targeting the Oncogenic TBX2 Transcription Factor With Chromomycins

“…However, CA 2 had an IC 50 of 18.8 nM in the metastatic melanoma cell line Malme-3M and was thus less cytotoxic than the CA 5 and CA 6 chromomycins tested in this study against melanoma cells (Guimarães et al, 2014). Furthermore, a recent study from our group compared the cytotoxicity of 4 different chromomycins in a 5 human tumor cell line panel and showed that CA 5 was the most potent, especially against the MM200 (IC 50 of 0.2 nM) and 501Mel (IC 50 of 0.8 nM) melanoma cells (Pinto et al, 2019).…”

“…Most of the available reports on this class of molecules regard the biological properties of CA 3 and, to a less extent, of CA 2 . These chromomycins are, in turn, stereoisomers of CA 6 and CA 5, respectively, as demonstrated by Pinto et al (2019) and Pettit et al (2015). CA 3 binds to the minor groove of the DNA complex as a dimer in a process dependent on Mg +2 , in which a portion of the chromophore along with the D, E and F sugar moieties interact with residues of the minor groove, while the A and B sugar moieties and another portion of the chromophore interact with the phosphate backbone (Gao and Patel, 1989;Boer et al, 2009).…”

“…The isolation and characterization of chromomycins A 5 (CA 5 ) and A 6 (CA 6 ) was previously described by Pinto et al (2019). The substances were resuspended in dimethyl sulfoxide (DMSO, Sigma Aldrich, USA).…”

“…They can also inhibit enzymes that are important for the maintenance of DNA integrity such as topoisomerases. Chromomycins are tricyclic glycosylated polyketides belonging to the aureolic acid family, with promising anticancer activity and antiproliferative properties (Guimarães et al, 2014;Pettit et al, 2015;Pinto et al, 2019). These molecules bind to the DNA minor groove, causing DNA damage of treated cells, enhancing the expression of apoptosis related genes (Boer et al, 2009;Zihlif et al, 2010).…”