Molecular Targets of Anticancer Agents from Filamentous Marine Cyanobacteria

Abstract

The prokaryotic marine cyanobacteria, especially the filamentous forms, are known to produce a plethora of structurally unique natural products. A majority of these molecules are nitrogen-containing, belonging to the hybrid polyketide-polypeptide structural class. Various activities of clinical significance have been attributed to these molecules, ranging from anticancer, neuromodulating to antiprotozoal properties. Particularly in the area of cancer therapy, a number of potent marine cyanobacterial compounds, including dolastatins 10, 15, and largazole, have been identified as anticancer drug leads and are being further developed synthetically for clinical usage. The high potencies of these compounds are due to their exquisite interactions or interference with cellular pathways, specific macromolecules, or enzymes, such as the JAK-STAT signaling pathway, histone deacetylase, proteasome, protein kinase C, actin and microtubule filaments. This mini review covers more than 90 references and features more than 40 anticancer compounds, consisting of marine cyanobacterial natural products and their synthetic analogues. Biological data of these compounds are discussed based on their molecular targets.

Depsipeptides Targeting Tumor Cells: Milestones from In Vitro to Clinical Trials

“…Likewise, dolastatin 15, a compound quite similar to dolastatin 10 (addressed in Section 2.5.2 and Section 3.4 herein), demonstrated an effect on growth and differentiation in leukemia cell lines and G 2 /M cell cycle arrest in human myeloma cell lines during in vivo trials [ 149 ]. However, further studies revealed that it was nearly seven times less active than its counterpart [ 140 ]. This slightly weaker in vivo activity was also reported for other molecules such as dolastatin 10 and isodolastatin H [ 248 ].…”

“…Microtubule–actin interactions are fundamental for many cellular processes such as cell motility, cell division, and cytoskeleton dynamics [ 139 ]. Many depsipeptides derived from bacteria exert activities against microfilaments, causing complete depolymerization of microtubules and hyper-polymerization of actin [ 140 ]. Moreover, they have shown the ability to destabilize microtubules, inducing caspase and Bcl-2 activation, eventually resulting in cell cycle arrest and apoptosis [ 141 ].…”

Absolute Stereochemistry of the β-Hydroxy Acid Unit in Hantupeptins and Trungapeptins

“…General: 1 H and 13 C NMR spectra were recorded on a 400 MHz Bruker NMR spectrometer in CDCl 3 (Cambridge Isotope Laboratories, Inc.), 99.8% D containing 0.03%, v/v, tetramethylsilane (TMS) and residual solvent signal (δ H at 7.26 ppm and δ C at 77.36 ppm) as internal standard. A linear gradient method, used for LCMS data to confirm the absolute stereochemical analysis of the hydrolysate, was carried out with a C 18 RP-HPLC column [Phenomenex Sphereclone 5 µm C 18 (2) 100 Å, 150 x 2.00 mm] using an Agilent 1100 series LC system coupled to a mass selective detector (MSD) ion trap XCT mass spectrometer equipped with an ESI interface system.…”

“…Marine cyanobacteria are a rich source of novel bioactive natural products for drug discovery and development [1]. Hantupeptins (1-3) and trungapeptins (4)(5)(6) are cyclic depsipeptides recently isolated from the marine cyanobacterium, Lyngbya majuscula (Figure 1) [2][3][4].…”

“…The addition of LiOH with H 2 O 2 produced LiOOH, which ensured cleavage of the auxiliary and yielded the free (2S,3R)-Hmoa (9) [11]. No purification of 9 was required as the removal of the auxiliary was complete based on 1 H NMR spectral data.…”