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

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

Seham S El-Hawary  1 , Ahmed M Sayed  2   3 , Rabab Mohammed  2 , Mohammad A Khanfar  4   5 , Mostafa E Rateb  2   6   7 , Tarek A Mohammed  8 , Dina Hajjar  9 , Hossam M Hassan  2   3 , Tobias A M Gulder  10   11 , Usama Ramadan Abdelmohsen  12
Affiliations

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

Seham S El-Hawary et al. Front Chem. .

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.

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Figures

Figure 1
Figure 1
Structures of isolated compounds.
Figure 2
Figure 2
HPLC profiles of actinomycetes extracts. (A) Saccharomonospora sp. UR22 and Dietzia sp. UR66 co-culture (B) Saccharomonospora sp. UR22 mono-culture (C) Dietzia sp. UR66 mono-culture.
Figure 3
Figure 3
1H-1H COSY, key HMBC, and NOESY correlations of compound (1).
Figure 4
Figure 4
1H-1H COSY, key HMBC, and NOESY correlations of compound (2).
Figure 5
Figure 5
Docking of compounds 1 (A,B) and 3 (C,D) within the ATP-binding site of Pim-1 kinase (PDB code 3umw). (E,F) The key binding interactions of Pim-1 co-crystallized ligand. The amino acid side chains were depicted in (A,C,E) for clarification.
See this image and copyright information in PMC

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