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

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

doi:10.3389/fchem.2018.00538

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

Front Chem. 2018 Nov 15:6:538. doi: 10.3389/fchem.2018.00538. eCollection 2018.

Authors

Seham S El-Hawary¹, Ahmed M Sayed^{2

3}, Rabab Mohammed², Mohammad A Khanfar^{4

5}, Mostafa E Rateb^{2

6

7}, Tarek A Mohammed⁸, Dina Hajjar⁹, Hossam M Hassan^{2

3}, Tobias A M Gulder^{10

11}, Usama Ramadan Abdelmohsen¹²

Affiliations

¹ Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
² Pharmacognosy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
³ Pharmacognosy Department, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt.
⁴ Faculty of Pharmacy, The University of Jordan, Amman, Jordan.
⁵ College of Pharmacy, Alfaisal University, Riyadh, Saudi Arabia.
⁶ School of Computing, Engineering and Physical Sciences, University of the West of Scotland, Paisley, United Kingdom.
⁷ Marine Biodiscovery Centre, University of Aberdeen, Aberdeen, United Kingdom.
⁸ Marine Invertebrates, National Institute of Oceanography and Fisheries, Red Sea Branch, Hurghada, Egypt.
⁹ Department of Biochemistry, Faculty of Science, Center for Science and Medical Research, University of Jeddah, Jeddah, Saudi Arabia.
¹⁰ Department of Chemistry and Center for Integrated Protein Science Munich (CIPSM), Biosystems Chemistry, Technical University of Munich, Garching, Germany.
¹¹ Chair of Technical Biochemistry, Technische Universität Dresden, Dresden, Germany.
¹² Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia, Egypt.

Abstract

Saccharomonospora sp. UR22 and Dietzia sp. UR66, two actinomycetes derived from the Red Sea sponge Callyspongia siphonella, were co-cultured and the induced metabolites were monitored by HPLC-DAD and TLC. Saccharomonosporine A (1), a novel brominated oxo-indole alkaloid, convolutamydine F (2) along with other three known induced metabolites (3-5) were isolated from the EtOAc extract of Saccharomonospora sp. UR22 and Dietzia sp. UR66 co-culture. Additionally, axenic culture of Saccharomonospora sp. UR22 led to isolation of six known microbial metabolites (6-11). A kinase inhibition assay results showed that compounds 1 and 3 were potent Pim-1 kinase inhibitors with an IC₅₀ value of 0.3 ± 0.02 and 0.95 ± 0.01 μM, respectively. Docking studies revealed the binding mode of compounds 1 and 3 in the ATP pocket of Pim-1 kinase. Testing of compounds 1 and 3 displayed significant antiproliferative activity against the human colon adenocarcinoma HT-29, (IC₅₀ 3.6 and 3.7 μM, respectively) and the human promyelocytic leukemia HL-60, (IC₅₀ 2.8 and 4.2 μM, respectively). These results suggested that compounds 1 and 3 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.

Keywords: Dietzia sp.; Pim-1 kinase; Saccharomonospora sp.; Saccharomonosporine A; actinomycetes; co-cultivation; convolutamydine F; docking.