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15 pages, 10165 KiB

Open AccessArticle

Octominin: A Novel Synthetic Anticandidal Peptide Derived from Defense Protein of Octopus minor

by Chamilani Nikapitiya, S.H.S. Dananjaya, H.P.S.U. Chandrarathna, Mahanama De Zoysa and Ilson Whang

Mar. Drugs 2020, 18(1), 56; https://doi.org/10.3390/md18010056 - 15 Jan 2020

Cited by 25 | Viewed by 4206

Abstract

The rapid emergence of multidrug-resistant pathogens makes an urgent need for discovering novel antimicrobial agents as alternatives to conventional antibiotics. Towards this end, we designed and synthesized a synthetic peptide of 23 amino acids (AAs) (¹GWLIRGAIHAGKAIHGLIHRRRH²³) from a defense [...] Read more.

The rapid emergence of multidrug-resistant pathogens makes an urgent need for discovering novel antimicrobial agents as alternatives to conventional antibiotics. Towards this end, we designed and synthesized a synthetic peptide of 23 amino acids (AAs) (¹GWLIRGAIHAGKAIHGLIHRRRH²³) from a defense protein 3 cDNA sequence of Octopus minor. The sequence of the peptide, which was named Octominin, had characteristic features of known antimicrobial peptides (AMPs) such as a positive charge (+5), high hydrophobic residue ratio (43%), and 1.86 kcal/mol of Boman index. Octominin was predicted to have an alpha-helix secondary structure. The synthesized Octominin was 2625.2 Da with 92.5% purity. The peptide showed a minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of 50 and 200 μg/mL, respectively, against Candida albicans. Field emission scanning electron microscopy observation confirmed that Octominin caused ultrastructural cell wall deformities in C. albicans. In addition, propidium iodide penetrated the Octominin-treated C. albicans cells, further demonstrating loss of cell membrane integrity that caused cell death at both MIC and MFC. Octominin treatment increased the production of intracellular reactive oxygen species and decreased cell viability in a concentration dependent manner. Cytotoxicity assays revealed no significant influence of Octominin on the viability of human embryonic kidney 293T cell line, with over 95% live cells in the Octominin-treated group observed up to 100 µg/mL. Moreover, we confirmed the antifungal action of Octominin in vivo using a zebrafish experimental infection model. Overall, our results demonstrate the Octominin is a lead compound for further studies, which exerts its effects by inducing cell wall damage, causing loss of cell membrane integrity, and elevating oxidative stress. Full article

(This article belongs to the Special Issue Synthetic and Biosynthetic Approaches to Marine Natural Products)

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14 pages, 3183 KiB

Open AccessArticle

Discovery of Geranylgeranyl Pyrophosphate Synthase (GGPPS) Paralogs from Haematococcus pluvialis Based on Iso-Seq Analysis and Their Function on Astaxanthin Biosynthesis

by Danqiong Huang, Wenfu Liu, Anguo Li, Chaogang Wang and Zhangli Hu

Mar. Drugs 2019, 17(12), 696; https://doi.org/10.3390/md17120696 - 12 Dec 2019

Cited by 12 | Viewed by 3298

Abstract

Haematococcus pluvialis is widely distributed in the world and well known as the richest natural source of astaxanthin that is a strong antioxidant with excellent commercial value. The pathway of astaxanthin biosynthesis in H. pluvialis has been documented as an enzymatic reaction. Several [...] Read more.

Haematococcus pluvialis is widely distributed in the world and well known as the richest natural source of astaxanthin that is a strong antioxidant with excellent commercial value. The pathway of astaxanthin biosynthesis in H. pluvialis has been documented as an enzymatic reaction. Several enzymes have been reported, but their isoforms or homologs have not been investigated genome-wide. To better understand the astaxanthin biosynthesis pathway in H. pluvialis, eight candidates of the geranylgeranyl pyrophosphate synthase gene (HpGGPPS) predicted from Iso-seq data were isolated in this study. The length of coding region of these candidates varied from 960 bp to 1272 bp, composing of 7–9 exons. The putative amino acids of all candidates composed the signature domain of GGPPS gene. However, the motifs in the domain region are varied, indicating different bio-functions. Phylogenetic analysis revealed eight candidates can be clustered into three groups. Only two candidates in Group1 encode the synthase participating in the astaxanthin formation. The yield of astaxanthin from these two candidates, 7.1 mg/g (DW) and 6.5 mg/g (DW) respectively, is significant higher than that from CrtE (2.4 mg/g DW), a GGPPS gene from Pantoea ananatis. This study provides a potential productive pathway for astaxanthin synthesis. Full article

(This article belongs to the Special Issue Synthetic and Biosynthetic Approaches to Marine Natural Products)

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16 pages, 2328 KiB

Open AccessCommunication

Hybrid Polyketides from a Hydractinia-Associated Cladosporium sphaerospermum SW67 and Their Putative Biosynthetic Origin

by Seoung Rak Lee, Dahae Lee, Hee Jeong Eom, Maja Rischer, Yoon-Joo Ko, Ki Sung Kang, Chung Sub Kim, Christine Beemelmanns and Ki Hyun Kim

Mar. Drugs 2019, 17(11), 606; https://doi.org/10.3390/md17110606 - 24 Oct 2019

Cited by 10 | Viewed by 3201

Abstract

Five hybrid polyketides (1a, 1b, and 2–4) containing tetramic acid core including a new hybrid polyketide, cladosin L (1), were isolated from the marine fungus Cladosporium sphaerospermum SW67, which was isolated from the marine hydroid [...] Read more.

Five hybrid polyketides (1a, 1b, and 2–4) containing tetramic acid core including a new hybrid polyketide, cladosin L (1), were isolated from the marine fungus Cladosporium sphaerospermum SW67, which was isolated from the marine hydroid polyp of Hydractinia echinata. The hybrid polyketides were isolated as a pair of interconverting geometric isomers. The structure of 1 was determined based on 1D and 2D NMR spectroscopic and HR-ESIMS analyses. Its absolute configuration was established by quantum chemical electronic circular dichroism (ECD) calculations and modified Mosher’s method. Tetramic acid-containing compounds are reported to be derived from a hybrid PKS-NRPS, which was also proved by analyzing our ¹³C-labeling data. We investigated whether compounds 1–4 could prevent cell damage induced by cisplatin, a platinum-based anticancer drug, in LLC-PK1 cells. Co-treatment with 2 and 3 ameliorated the damage of LLC-PK1 cells induced by 25 μM of cisplatin. In particular, the effect of compound 2 at 100 μM (cell viability, 90.68 ± 0.81%) was similar to the recovered cell viability of 88.23 ± 0.25% with 500 μM N-acetylcysteine (NAC), a positive control. Full article

(This article belongs to the Special Issue Synthetic and Biosynthetic Approaches to Marine Natural Products)

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16 pages, 7206 KiB

Open AccessArticle

Synthesis and Antitumor Activity Evaluation of Compounds Based on Toluquinol

by Iván Cheng-Sánchez, José A. Torres-Vargas, Beatriz Martínez-Poveda, Guillermo A. Guerrero-Vásquez, Miguel Ángel Medina, Francisco Sarabia and Ana R. Quesada

Mar. Drugs 2019, 17(9), 492; https://doi.org/10.3390/md17090492 - 23 Aug 2019

Cited by 5 | Viewed by 2960

Abstract

Encouraged by the promising antitumoral, antiangiogenic, and antilymphangiogenic properties of toluquinol, a set of analogues of this natural product of marine origin was synthesized to explore and evaluate the effects of structural modifications on their cytotoxic activity. We decided to investigate the effects [...] Read more.

Encouraged by the promising antitumoral, antiangiogenic, and antilymphangiogenic properties of toluquinol, a set of analogues of this natural product of marine origin was synthesized to explore and evaluate the effects of structural modifications on their cytotoxic activity. We decided to investigate the effects of the substitution of the methyl group by other groups, the introduction of a second substituent, the relative position of the substituents, and the oxidation state. A set of analogues of 2-substituted, 2,3-disubstituted, and 2,6-disubstituted derived from hydroquinone were synthesized. The results revealed that the cytotoxic activity of this family of compounds could rely on the hydroquinone/benzoquinone part of the molecule, whereas the substituents might modulate the interaction of the molecule with their targets, changing either its activity or its selectivity. The methyl group is relevant for the cytotoxicity of toluquinol, since its replacement by other groups resulted in a significant loss of activity, and in general the introduction of a second substituent, preferentially in the para position with respect to the methyl group, was well tolerated. These findings provide guidance for the design of new toluquinol analogues with potentially better pharmacological properties. Full article

(This article belongs to the Special Issue Synthetic and Biosynthetic Approaches to Marine Natural Products)

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10 pages, 1340 KiB

Open AccessArticle

Syntheses of Benzo[d]Thiazol-2(3H)-One Derivatives and Their Antidepressant and Anticonvulsant Effects

by Qinghao Jin, Zhiyang Fu, Liping Guan and Haiying Jiang

Mar. Drugs 2019, 17(7), 430; https://doi.org/10.3390/md17070430 - 23 Jul 2019

Cited by 13 | Viewed by 3177

Abstract

Thirty-four new benzo[d]thiazol derivatives 2a–2i, 3a–3r, and 4a–4g were synthesized and investigated for their potential antidepressant and anticonvulsant effects. In a forced swimming test, 2c and 2d showed the highest antidepressant and anticonvulsant [...] Read more.

Thirty-four new benzo[d]thiazol derivatives 2a–2i, 3a–3r, and 4a–4g were synthesized and investigated for their potential antidepressant and anticonvulsant effects. In a forced swimming test, 2c and 2d showed the highest antidepressant and anticonvulsant effects. 2c and 2d displayed a higher percentage decrease in immobility duration (89.96% and 89.62%, respectively) than that of fluoxetine (83.62%). In the maximal electroshock seizure test, 3n and 3q showed the highest anticonvulsant effect, with ED₅₀ values of 46.1 and 64.3 mg kg⁻¹, and protective indices of 6.34 and 4.11, respectively, which were similar to those of phenobarbital or valproate. We also found that the mechanism for the antidepressant activity of 2c and 2d may be via increasing the concentrations of serotonin and norepinephrine. Full article

(This article belongs to the Special Issue Synthetic and Biosynthetic Approaches to Marine Natural Products)

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15 pages, 1406 KiB

Open AccessArticle

Short Chain Fatty Acid Biosynthesis in Microalgae Synechococcus sp. PCC 7942

by Yi Gong and Xiaoling Miao

Mar. Drugs 2019, 17(5), 255; https://doi.org/10.3390/md17050255 - 28 Apr 2019

Cited by 22 | Viewed by 4209

Abstract

Short chain fatty acids (SCFAs) are valued as a functional material in cosmetics. Cyanobacteria can accumulate SCFAs under some conditions, the related mechanism is unclear. Two potential genes Synpcc7942_0537 (fabB/F) and Synpcc7942_1455 (fabH) in Synechococcus sp. PCC 7942 have [...] Read more.

Short chain fatty acids (SCFAs) are valued as a functional material in cosmetics. Cyanobacteria can accumulate SCFAs under some conditions, the related mechanism is unclear. Two potential genes Synpcc7942_0537 (fabB/F) and Synpcc7942_1455 (fabH) in Synechococcus sp. PCC 7942 have homology with fabB/F and fabH encoding β-ketoacyl ACP synthases (I/II/III) in plants. Therefore, effects of culture time and cerulenin on SCFAs accumulation, expression levels and functions of these two potential genes were studied. The results showed Synechococcus sp. PCC 7942 accumulated high SCFAs (C12 + C14) in early growth stage (day 4) and at 7.5g/L cerulenin concentration, reaching to 2.44% and 2.84% of the total fatty acids respectively, where fabB/F expression was down-regulated. Fatty acid composition analysis showed C14 increased by 65.19% and 130% respectively, when fabB/F and fabH were antisense expressed. C14 increased by 10.79% (fab(B/F)⁻) and 6.47% (fabH⁻) under mutation conditions, while C8 increased by six times in fab(B/F)⁻ mutant strain. These results suggested fabB/F is involved in fatty acid elongation (C <18) and the elongation of cis-16:1 to cis-18:1 fatty acid in Synechococcus sp. PCC 7942, while fabH was involved in elongation of fatty acid synthesis, which were further confirmed in complementary experiments of E. coli. The research could provide the scientific basis for the breeding of SCFA-rich microalgae species. Full article

(This article belongs to the Special Issue Synthetic and Biosynthetic Approaches to Marine Natural Products)

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14 pages, 1161 KiB

Open AccessArticle

A General Strategy for the Stereoselective Synthesis of the Furanosesquiterpenes Structurally Related to Pallescensins 1–2

by Stefano Serra

Mar. Drugs 2019, 17(4), 245; https://doi.org/10.3390/md17040245 - 25 Apr 2019

Cited by 5 | Viewed by 3249

Abstract

Here, we describe a general stereoselective synthesis of the marine furanosesquiterpenes structurally related to pallescensins 1–2. The stereoisomeric forms of the pallescensin 1, pallescensin 2, and dihydropallescensin 2 were obtained in high chemical and isomeric purity, whereas isomicrocionin-3 was synthesized for the first [...] Read more.

Here, we describe a general stereoselective synthesis of the marine furanosesquiterpenes structurally related to pallescensins 1–2. The stereoisomeric forms of the pallescensin 1, pallescensin 2, and dihydropallescensin 2 were obtained in high chemical and isomeric purity, whereas isomicrocionin-3 was synthesized for the first time. The sesquiterpene framework was built up by means of the coupling of the C₁₀ cyclogeranyl moiety with the C₅ 3-(methylene)furan moiety. The key steps of our synthetic procedure are the stereoselective synthesis of four cyclogeraniol isomers, their conversion into the corresponding cyclogeranylsulfonylbenzene derivatives, their alkylation with 3-(chloromethyl)furan, and the final reductive cleavage of the phenylsulfonyl functional group to afford the whole sesquiterpene framework. The enantioselective synthesis of the α-, 3,4-dehydro-γ- and γ-cyclogeraniol isomers was performed using both a lipase-mediated resolution procedure and different regioselective chemical transformations. Full article

(This article belongs to the Special Issue Synthetic and Biosynthetic Approaches to Marine Natural Products)

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11 pages, 2071 KiB

Open AccessArticle

Synthesis of Polysubstituted Tetrahydropyrans by Stereoselective Hydroalkoxylation of Silyl Alkenols: En Route to Tetrahydropyranyl Marine Analogues

by Carlos Díez-Poza, Patricia Val, Francisco J. Pulido and Asunción Barbero

Mar. Drugs 2018, 16(11), 421; https://doi.org/10.3390/md16110421 - 01 Nov 2018

Cited by 3 | Viewed by 2718

Abstract

Tetrahydropyrans are abundantly found in marine natural products. The interesting biological properties of these compounds and their analogues make necessary the development of convenient procedures for their synthesis. In this paper, an atom economy access to tetrahydropyrans by intramolecular acid-mediated cyclization of silylated [...] Read more.

Tetrahydropyrans are abundantly found in marine natural products. The interesting biological properties of these compounds and their analogues make necessary the development of convenient procedures for their synthesis. In this paper, an atom economy access to tetrahydropyrans by intramolecular acid-mediated cyclization of silylated alkenols is described. p-TsOH has shown to be an efficient reagent to yield highly substituted tetrahydropyrans. Moreover, excellent diastereoselectivities are obtained both for unsubstituted and alkylsubstituted vinylsilyl alcohols. The methodology herein developed may potentially be applied to the synthesis of marine drugs derivatives. Full article

(This article belongs to the Special Issue Synthetic and Biosynthetic Approaches to Marine Natural Products)

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20 pages, 2923 KiB

Open AccessArticle

Asymmetric Synthesis of the C15–C32 Fragment of Alotamide and Determination of the Relative Stereochemistry

by Hao-yun Shi, Yang Xie, Pei Hu, Zi-qiong Guo, Yi-hong Lu, Yu Gao and Cheng-gang Huang

Mar. Drugs 2018, 16(11), 414; https://doi.org/10.3390/md16110414 - 30 Oct 2018

Cited by 5 | Viewed by 3271

Abstract

Alotamide is a cyclic depsipetide isolated from a marine cyanobacterium and possesses a unique activation of calcium influx in murine cerebrocortical neurons (EC₅₀ 4.18 µM). Due to its limited source, the three stereocenters (C19, C28, and C30) in its polyketide fragment remain [...] Read more.

Alotamide is a cyclic depsipetide isolated from a marine cyanobacterium and possesses a unique activation of calcium influx in murine cerebrocortical neurons (EC₅₀ 4.18 µM). Due to its limited source, the three stereocenters (C19, C28, and C30) in its polyketide fragment remain undetermined. In this study, the first asymmetric synthesis of its polyketide fragment was achieved. Four relative possible diastereomers were constructed with a boron-mediated enantioselective aldol reaction and Julia–Kocienski olefination as the key steps. Comparison of ¹³C NMR spectra revealed the relative structure of fragment C15–C32 of alotamide. Full article

(This article belongs to the Special Issue Synthetic and Biosynthetic Approaches to Marine Natural Products)

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14 pages, 4586 KiB

Open AccessArticle

Smenamide A Analogues. Synthesis and Biological Activity on Multiple Myeloma Cells

by Alessia Caso, Ilaria Laurenzana, Daniela Lamorte, Stefania Trino, Germana Esposito, Vincenzo Piccialli and Valeria Costantino

Mar. Drugs 2018, 16(6), 206; https://doi.org/10.3390/md16060206 - 13 Jun 2018

Cited by 11 | Viewed by 4291

Abstract

Smenamides are an intriguing class of peptide/polyketide molecules of marine origin showing antiproliferative activity against lung cancer Calu-1 cells at nanomolar concentrations through a clear pro-apoptotic mechanism. To probe the role of the activity-determining structural features, the 16-epi-analogue of smenamide A [...] Read more.

Smenamides are an intriguing class of peptide/polyketide molecules of marine origin showing antiproliferative activity against lung cancer Calu-1 cells at nanomolar concentrations through a clear pro-apoptotic mechanism. To probe the role of the activity-determining structural features, the 16-epi-analogue of smenamide A and eight simplified analogues in the 16-epi series were prepared using a flexible synthetic route. The synthetic analogues were tested on multiple myeloma (MM) cell lines showing that the configuration at C-16 slightly affects the activity, since the 16-epi-derivative is still active at nanomolar concentrations. Interestingly, it was found that the truncated compound 8, mainly composed of the pyrrolinone terminus, was not active, while compound 13, essentially lacking the pyrrolinone moiety, was 1000-fold less active than the intact substance and was the most active among all the synthesized compounds. Full article

(This article belongs to the Special Issue Synthetic and Biosynthetic Approaches to Marine Natural Products)

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Review

Jump to: Research

22 pages, 6766 KiB

Open AccessReview

Marine-Derived Natural Lead Compound Disulfide-Linked Dimer Psammaplin A: Biological Activity and Structural Modification

by Qinxue Jing, Xu Hu, Yanzi Ma, Jiahui Mu, Weiwei Liu, Fanxing Xu, Zhanlin Li, Jiao Bai, Huiming Hua and Dahong Li

Mar. Drugs 2019, 17(7), 384; https://doi.org/10.3390/md17070384 - 27 Jun 2019

Cited by 28 | Viewed by 4928

Abstract

Marine natural products are considered to be valuable resources that are furnished with diverse chemical structures and various bioactivities. To date, there are seven compounds derived from marine natural products which have been approved as therapeutic drugs by the U.S. Food and Drug [...] Read more.

Marine natural products are considered to be valuable resources that are furnished with diverse chemical structures and various bioactivities. To date, there are seven compounds derived from marine natural products which have been approved as therapeutic drugs by the U.S. Food and Drug Administration. Numerous bromotyrosine derivatives have been isolated as a type of marine natural products. Among them, psammaplin A, including the oxime groups and carbon–sulfur bonds, was the first identified symmetrical bromotyrosine-derived disulfide dimer. It has been found to have a broad bioactive spectrum, especially in terms of antimicrobial and antiproliferative activities. The highest potential indole-derived psammaplin A derivative, UVI5008, is used as an epigenetic modulator with multiple enzyme inhibitory activities. Inspired by these reasons, psammaplin A has gradually become a research focus for pharmacologists and chemists. To the best of our knowledge, there is no systematic review about the biological activity and structural modification of psammaplin A. In this review, the pharmacological effects, total synthesis, and synthesized derivatives of psammaplin A are summarized. Full article

(This article belongs to the Special Issue Synthetic and Biosynthetic Approaches to Marine Natural Products)

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