Structure-Activity Relationship of Cytotoxic Natural Products from Indonesian Marine Sponges.

Indonesian marine natural products have been one of the most promising sources in the race to obtain potential drugs for cancer treatment. One of the primary producers of cytotoxic compounds is sponges. However, there are still limited sources of comprehensive reviews related to the relationship between the structure of isolated compounds and their cytotoxic activity. This review remarks the attempt to provide a preliminary guidance from the perspective of structure-activity relationship and its participation on marine natural products research. This guidance is segregated by the compound's classes and their cytotoxic targets to obtain and organized a reliable summary of inter-study of the isolated compounds and their cytotoxicity. Structure-activity relationship is well-known for its ability to tune the bioactivity of a specific compound, especially on synthetic organic chemistry and in silico study but rarely used on natural product chemistry. The present review is intended to narrow down the endless possibilities of cytotoxicity by giving a predictable structure-activity relationship for active compounds. In addition, bioactive framework leads were selected by uncovering a noticeable structure-activity relationship with the intervention of cytotoxic agents from natural sources, especially Indonesian marine sponge.

Ecological and Pharmacological Activities of Polybrominated Diphenyl Ethers (PBDEs) from the Indonesian Marine Sponge Lamellodysidea herbacea.

Two known Polybrominated Diphenyl Ethers (PBDEs), 3,4,5-tribromo-2-(2',4'-dibromophenoxy)phenol (1d) and 3,4,5,6-tetrabromo-2-(2',4'-dibromophenoxy)phenol (2b), were isolated from the Indonesian marine sponge Lamellodysidea herbacea. The structure was confirmed using 13C chemical shift average deviation and was compared to the predicted structures and recorded chemical shifts in previous studies. We found a wide range of bioactivities from the organic crude extract, such as (1) a strong deterrence against the generalist pufferfish Canthigaster solandri, (2) potent inhibition against environmental and human pathogenic bacterial and fungal strains, and (3) the inhibition of the Hepatitis C Virus (HCV). The addition of a bromine atom into the A-ring of compound 2b resulted in higher fish feeding deterrence compared to compound 1d. On the contrary, compound 2b showed only more potent inhibition against the Gram-negative bacteria Rhodotorula glutinis (MIC 2.1 µg/mL), while compound 1d showed more powerful inhibition against the other human pathogenic bacteria and fungi. The first report of a chemical defense by compounds 1d and 2b against fish feeding and environmental relevant bacteria, especially pathogenic bacteria, might be one reason for the widespread occurrence of the shallow water sponge Lamellodysidea herbacea in Indonesia and the Indo-Pacific.

Anti-Infective and Antiviral Activity of Valinomycin and Its Analogues from a Sea Cucumber-Associated Bacterium, Streptomyces sp. SV 21.

The manuscript investigated the isolation, characterization and anti-infective potential of valinomycin (3), streptodepsipeptide P11A (2), streptodepsipeptide P11B (1), and one novel valinomycin analogue, streptodepsipeptide SV21 (4), which were all produced by the Gram-positive strain Streptomycescavourensis SV 21. Although the exact molecular weight and major molecular fragments were recently reported for compound 4, its structure elucidation was not based on compound isolation and spectroscopic techniques. We successfully isolated and elucidated the structure based on the MS2 fragmentation pathways as well as 1H and 13C NMR spectra and found that the previously reported structure of compound 4 differs from our analysis. Our findings showed the importance of isolation and structure elucidation of bacterial compounds in the era of fast omics technologies. The here performed anti-infective assays showed moderate to potent activity against fungi, multi drug resistant (MDR) bacteria and infectivity of the Hepatitis C Virus (HCV). While compounds 2, 3 and 4 revealed potent antiviral activity, the observed minor cytotoxicity needs further investigation. Furthermore, the here performed anti-infective assays disclosed that the symmetry of the valinomycin molecule is most important for its bioactivity, a fact that has not been reported so far.

Biotechnological Potential of Bacteria Isolated from the Sea Cucumber Holothuria leucospilota and Stichopus vastus from Lampung, Indonesia.

In order to minimize re-discovery of already known anti-infective compounds, we focused our screening approach on understudied, almost untapped marine environments including marine invertebrates and their associated bacteria. Therefore, two sea cucumber species, Holothuria leucospilota and Stichopus vastus, were collected from Lampung (Indonesia), and 127 bacterial strains were identified by partial 16S rRNA-gene sequencing analysis and compared with the NCBI database. In addition, the overall bacterial diversity from tissue samples of the sea cucumbers H. leucospilota and S. vastus was analyzed using the cultivation-independent Illumina MiSEQ analysis. Selected bacterial isolates were grown to high densities and the extracted biomass was tested against a selection of bacteria and fungi as well as the hepatitis C virus (HCV). Identification of putative bioactive bacterial-derived compounds were performed by analyzing the accurate mass of the precursor/parent ions (MS1) as well as product/daughter ions (MS2) using high resolution mass spectrometry (HRMS) analysis of all active fractions. With this attempt we were able to identify 23 putatively known and two previously unidentified precursor ions. Moreover, through 16S rRNA-gene sequencing we were able to identify putatively novel bacterial species from the phyla Actinobacteria, Proteobacteria and also Firmicutes. Our findings suggest that sea cucumbers like H. leucospilota and S. vastus are promising sources for the isolation of novel bacterial species that produce compounds with potentially high biotechnological potential.

Isolation, Structure Elucidation and Biological Evaluation of Lagunamide D: A New Cytotoxic Macrocyclic Depsipeptide from Marine Cyanobacteria.

Lagunamide D, a new cytotoxic macrocyclic depsipeptide, was discovered from a collection of marine cyanobacteria from Loggerhead Key in the Dry Tortugas, Florida. An intramolecular ester exchange was observed, where the 26-membered macrocycle could contract to a 24-membered compound via acyl migration at the 1,3-diol unit, and the transformation product was named lagunamide D'. The planar structures of both compounds were elucidated using a combination of nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectroscopy (HRMS). The absolute configurations were determined on the basis of enantioselective analysis, modified Mosher's analysis, Kishi NMR database, and direct comparison with lagunamide A, a structure closely resembling lagunamide D. Lagunamides A and D displayed low-nanomolar antiproliferative activity against A549 human lung adenocarcinoma cells, while the structural transformation from the 26-membered lagunamide D macrocycle to the 24-membered ring structure for lagunamide D' led to a 9.6-fold decrease in activity. Lagunamide D also displayed potent activity in triggering apoptosis in a dose- and time-dependent manner. Further investigation on the mechanism of action of the lagunamide scaffold is needed to fully explore its therapeutic potential as an anticancer agent.