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Akunolides A ( 1 ), B ( 2 ), C ( 3 ), and D ( 4 ), new macrolide glycosides, were isolated from a marine Okeania sp. cyanobacterium. Their structures were elucidated by spectroscopic analyses and derivatization reactions. Akunolides A-D ( 1 - 4 ) are classified as 16-membered macrolide glycosides, which are relatively rare structures for marine cyanobacterium-derived natural products. Akunolides A-D ( 1 - 4 ) showed moderate antitrypanosomal activities against Trypanosoma brucei rhodesiense , with IC 50 values ranging from 11 to 14 μM. Furthermore, akunolides A ( 1 ) and C ( 3 ) exhibited no cytotoxicity against normal human WI-38 cells even at a concentration of 150 μM.

Irijimasides A-E ( 1 - 5 ), a series of new 14-membered macrolide glycosides, were isolated from a marine cyanobacterium collected in Okinawa. The gross structures of 1 - 5 were established by spectroscopic analysis, including 2D NMR, while absolute stereostructures were determined based on NOESY spectra, chemical derivatization, and ECD data. All five macrolides suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP) activity in mouse RAW264 macrophage cells, indicating that these compounds inhibit osteoclast formation.

Iriomoteolide-2a is a marine macrolide metabolite isolated from a cultured broth of the benthic dinoflagellate Amphidinium sp. HYA024 strain. This naturally occurring substance was reported to show remarkable cytotoxic activity against human cancer cell lines HeLa and DG-75 and in vivo antitumor activity against murine leukemia P388 cell line. Herein, the total synthesis, stereochemical revision, and biological assessment of iriomoteolide-2a are reported in detail. Total synthesis of the proposed structure 1 of iriomoteolide-2a featured a late-stage convergent assembly of three components by a Suzuki-Miyaura coupling, an esterification, and a ring-closing metathesis. However, the NMR data of synthetic 1 were not identical to those of the natural product. Careful analysis of the NMR data of the authentic material and synthesis/NMR analysis of appropriately designed model compounds led to consideration of four possible stereoisomers 2-5 as candidates for the correct structure. Accordingly, total syntheses of 2-5 were achieved by taking advantage of the convergent strategy, and comparison of the NMR spectra of synthetic 2-5 with those of the natural product led to the conclusion that 5 shows the correct relative configuration of iriomoteolide-2a. The absolute configuration of this natural product was finally established through chiral HPLC analysis of synthetic 5/ent-5 with the authentic sample. The antiproliferative activity of the synthetic compounds was assessed against HeLa and A549 cells to show that, in contrast to expectation, synthetic 5 and ent-5 were only marginally active in these cell lines. This work clearly underscores the vital role of total synthesis in the establishment of the structure and biological activity of natural products., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Biselyngbyaside, an 18-membered macrolide glycoside from marine cyanobacteria, and its derivatives are known to be sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA) inhibitors. Recently, a SERCA orthologue of the malaria parasite, PfATP6, has attracted attention as a malarial drug target. To provide a novel drug lead, we designed new synthetic analogs of biselyngbyolide B, the aglycone of biselyngbyaside, based on the co-crystal structure of SERCA with biselyngbyolide B, and synthesized them using the established synthetic route for biselyngbyolide B. Their biological activities against malarial parasites were evaluated., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Four new macrolactones, leptolyngbyolides A-D, were isolated from the cyanobacterium Leptolyngbya sp. collected in Okinawa, Japan. The planar structures of leptolyngbyolides were determined by extensive NMR studies, although complete assignment of the absolute configuration awaited the catalytic asymmetric total synthesis of leptolyngbyolide C. The synthesis took advantage of the catalytic asymmetric thioamide-aldol reaction using copper(I) complexed with a chiral bidentate phosphine ligand to regulate two key stereochemistries of the molecule at the outset. The present total synthesis demonstrates the utility of this reaction for the construction of complex chemical entities. In addition to the total synthesis, this work reports that leptolyngbyolides depolymerize filamentous actin (F-actin) both in vitro and in cells. Detailed biological studies suggest the probable order of F-actin depolymerization and apoptosis caused by leptolyngbyolides., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Biselyngbyasides (BLSs), macrolides from a marine cyanobacterium, are cytotoxic natural products whose target molecule is unknown. Here we report that BLSs are high affinity (Ki∼10 nM) inhibitors of Ca(2+)-pumps with a unique binding mode. The crystal structures of the Ca(2+)-pump in complex with BLSs at 3.2-3.5 Å-resolution show that BLSs bind to the pump near the cytoplasmic surface of the transmembrane region. The crystal structures and activity measurement of BLS analogs allow us to identify the structural features that confer high potency to BLSs as inhibitors of the pump., (Copyright © 2015. Published by Elsevier B.V.)

Biselyngbyolide A is an 18-membered macrolide that exhibits significant biological activities such as growth-inhibitory activity and apoptosis inducing activity against cancer cells. In this study, the first total synthesis of biselyngbyolide A by using an intramolecular Stille coupling reaction as a key step is achieved.

Aplyronine A (1) and mycalolide B (2), which are cytotoxic actin-depolymerizing marine macrolides, were revealed to induce apoptosis in human leukemia HL60 cells and human epithelial carcinoma HeLa S(3) cells. Based on these results, actin-depolymerizing compounds were expected to exhibit apoptosis-inducing activity in cancer cells. Compounds 3-6, which were synthesized based on the side-chain structure of aplyronine A, were evaluated for their actin-depolymerizing activities in vitro and cytotoxicities against HL60 cells. The growth-inhibitory activities of 3-6 were well correlated with their actin-depolymerizing activities, and derivative 6 was shown to induce the disruption of actin filaments and apoptosis in HL60 cells. These results suggested that actin-depolymerizing agents 1, 2, and 6-induced apoptosis in HL60 cells may have been due to their actin-depolymerizing activity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The mass and function of bones depend on the maintenance of a complicated balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. An inhibitor of osteoclast differentiation and/or function is expected to be useful for treatment of bone lytic diseases such as osteoporosis, rheumatoid arthritis, and tumor metastasis into bone. Biselyngbyaside is a recently isolated macrolide compound from marine cyanobacteria Lyngbya sp. that shows wide-spectrum cytotoxicity toward human tumor cell lines. In this study, we investigated the effects of biselyngbyaside on osteoclast differentiation and function. Biselyngbyaside inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in mouse monocytic RAW264 cells and primary bone marrow-derived macrophages at a low concentration. Similarly, biselyngbyaside suppressed osteoblastic cell-mediated osteoclast differentiation in cocultures. In the RANKL-induced signaling pathway, biselyngbyaside inhibited the expression of c-Fos and NFATc1, which are important transcription factors in osteoclast differentiation. In mature osteoclasts, biselyngbyaside decreased resorption-pit formation. Biselyngbyaside also induced apoptosis accompanied by the induction of caspase-3 activation and nuclear condensation, and these effects were negated by the pancaspase inhibitor z-VAD-FMK. Taken together, the present findings indicate that biselyngbyaside suppresses bone resorption via inhibition of osteoclastogenesis and induction of apoptosis. Thus, biselyngbyaside may be useful for the prevention of bone lytic diseases., (Copyright © 2011 Wiley Periodicals, Inc.)

Bioassay-guided fractionation of the cytotoxic constituents of the marine cyanobacterium Lyngbya sp. led to the isolation of biselyngbyaside (1), a new 18-membered macrolide glycoside. The structure of 1 was established by spectroscopic analysis including 2D-NMR techniques and by synthetic studies. Biselyngbyaside (1) exhibits broad-spectrum cytotoxicity in a human tumor cell line panel.

The artificial actin-depolymerizing compounds 3-6, based on aplyronine A, an actin-depolymerizing antitumor marine macrolide, were synthesized, and their actin-depolymerizing activities and cytotoxicities were evaluated.

Aplyronines A-H are cytotoxic macrolides isolated from the sea hare Aplysia kurodai. Aplyronine A is the major constituent among the aplyronines, and this review concentrates on the results of chemical and biological research into this natural product. The isolation, determination of stereostructure and enantioselective total synthesis of the aplyronines are covered, together with discussion of their antitumour activity and structure-activity relationships, and the three-dimensional X-ray structure of the actin-aplyronine A complex.