AUTHOR=El-Hawary Seham S. , Sayed Ahmed M. , Mohammed Rabab , Khanfar Mohammad A. , Rateb Mostafa E. , Mohammed Tarek A. , Hajjar Dina , Hassan Hossam M. , Gulder Tobias A. M. , Abdelmohsen Usama Ramadan 

TITLE=New Pim-1 Kinase Inhibitor From the Co-culture of Two Sponge-Associated Actinomycetes

JOURNAL=Frontiers in Chemistry

VOLUME=6

YEAR=2018

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2018.00538

DOI=10.3389/fchem.2018.00538

ISSN=2296-2646

ABSTRACT=<p><italic>Saccharomonospora</italic> sp. UR22 and <italic>Dietzia</italic> sp. UR66, two actinomycetes derived from the Red Sea sponge <italic>Callyspongia siphonella</italic>, were co-cultured and the induced metabolites were monitored by HPLC-DAD and TLC. Saccharomonosporine A (<bold>1</bold>), a novel brominated oxo-indole alkaloid, convolutamydine F (<bold>2</bold>) along with other three known induced metabolites (<bold>3-5</bold>) were isolated from the EtOAc extract of <italic>Saccharomonospora</italic> sp. UR22 and <italic>Dietzia</italic> sp. UR66 co-culture. Additionally, axenic culture of <italic>Saccharomonospora</italic> sp. UR22 led to isolation of six known microbial metabolites (<bold>6-11</bold>). A kinase inhibition assay results showed that compounds <bold>1</bold> and <bold>3</bold> were potent Pim-1 kinase inhibitors with an IC<sub>50</sub> value of 0.3 ± 0.02 and 0.95 ± 0.01 μM, respectively. Docking studies revealed the binding mode of compounds <bold>1</bold> and <bold>3</bold> in the ATP pocket of Pim-1 kinase. Testing of compounds <bold>1</bold> and <bold>3</bold> displayed significant antiproliferative activity against the human colon adenocarcinoma HT-29, (IC<sub>50</sub> 3.6 and 3.7 μM, respectively) and the human promyelocytic leukemia HL-60, (IC<sub>50</sub> 2.8 and 4.2 μM, respectively). These results suggested that compounds <bold>1</bold> and <bold>3</bold> act as potential Pim-1 kinase inhibitors that mediate the tumor cell growth inhibitory effect. This study highlighted the co-cultivation approach as an effective strategy to increase the chemical diversity of the secondary metabolites hidden in the genomes of the marine actinomycetes.</p>