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Natural and Semi-Synthetic Small Molecules in Drug Discovery

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioactives and Nutraceuticals".

Deadline for manuscript submissions: closed (30 September 2018) | Viewed by 69158

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Special Issue Editor

Prof. Dr. David M. Pereira

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Guest Editor

Laboratory of Pharmacognosy, Faculty of Pharmacy, University of Porto, Porto, Portugal
Interests: natural products chemistry; bioactive small molecules; anti-inflammatory drugs; pro-apoptotic drugs; endoplasmic reticulum stress; proteasome inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Small molecules continue to be the most relevant set of therapeutic options for most human pathologies.

The process of drug discovery is complex and can arise from several strategies; however, naturally-occurring molecules are still one of the most prolific sources new chemical entities with application in human health. However, these molecules can frequently be upgraded or enhanced in their potency and selectivity by conducting structural changes. For this reason, derivatives obtained by hemisynthesis are also pivotal players in the process of drug discovery and development.

This Special Issue will focus in the process of drug discovery from naturally-occurring bioactive small molecules and also their hemisynthetic derivatives. Several diseases will be addressed including, but not limited to, cancer, as well as inflammatory, neurodegenerative and metabolic diseases.

Prof. Dr. David Pereira
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Bioactive small molecules
Natural molecules
Natural products chemistry
Hemisynthesis
Medicinal chemistry
Cancer
Inflammation
Neurodegenerative diseases
Metabolic diseases

Published Papers (12 papers)

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Research

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17 pages, 7625 KiB

Open AccessArticle

High Throughput Identification of Novel Conotoxins from the Vermivorous Oak Cone Snail (Conus quercinus) by Transcriptome Sequencing

by Bingmiao Gao, Chao Peng, Yabing Zhu, Yuhui Sun, Tian Zhao, Yu Huang and Qiong Shi

Int. J. Mol. Sci. 2018, 19(12), 3901; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19123901 - 05 Dec 2018

Cited by 19 | Viewed by 3416

Abstract

The primary objective of this study was to realize the large-scale discovery of conotoxin sequences from different organs (including the venom duct, venom bulb and salivary gland) of the vermivorous Oak cone snail, Conus quercinus. Using high-throughput transcriptome sequencing, we identified 133 putative conotoxins that belong to 34 known superfamilies, of which nine were previously reported while the remaining 124 were novel conotoxins, with 17 in new and unassigned conotoxin groups. A-, O₁-, M-, and I₂- superfamilies were the most abundant, and the cysteine frameworks XIII and VIII were observed for the first time in the A- and I₂-superfamilies. The transcriptome data from the venom duct, venom bulb and salivary gland showed considerable inter-organizational variations. Each organ had many exclusive conotoxins, and only seven of all the inferred mature peptides were common in the three organs. As expected, most of the identified conotoxins were synthesized in the venom duct at relatively high levels; however, a number of conotoxins were also identified in the venom bulb and the salivary gland with very low transcription levels. Therefore, various organs have different conotoxins with high diversity, suggesting greater contributions from several organs to the high-throughput discovery of new conotoxins for future drug development. Full article

(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)

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19 pages, 1659 KiB

Open AccessArticle

Synthesis and Transformation of (-)-Isopulegol-Based Chiral β-Aminolactones and β-Aminoamides

by Tam Minh Le, Péter Bérdi, István Zupkó, Ferenc Fülöp and Zsolt Szakonyi

Int. J. Mol. Sci. 2018, 19(11), 3522; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113522 - 08 Nov 2018

Cited by 9 | Viewed by 2892

Abstract

A library of isopulegol-based β-amino acid derivatives has been developed from commercially-available (-)-isopulegol. Michael addition of primary and secondary amines towards α,β-unsaturated γ-lactones was accomplished resulting in β-aminolactones in highly-stereoselective reactions. Ring-opening of β-aminolactones with different amines furnished excellent yields of β-aminoamides. Moreover, the applicability of aminolactones in peptide synthesis was examined by opening the lactone ring with α- and β-aminoesters, providing dipeptides as promising chiral substrates for the synthesis of foldamers. The antiproliferative activities of β-aminolactones and β-aminoamides were explored, and the structure-activity relationships were studied from the aspects of the stereochemistry of the monoterpene ring and the substituent effects on the β-aminoamide ring system. The N-unsubstituted (-)-isopulegol-based β-aminoamides exhibited considerable antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF7 and MDA-MB-231). Full article

(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)

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13 pages, 1979 KiB

Open AccessArticle

Chemical Identification of Isoflavonoids from a Termite-Associated Streptomyces sp. RB1 and Their Neuroprotective Effects in Murine Hippocampal HT22 Cell Line

by Seoung Rak Lee, Ji Hoon Song, Jae-Hyoung Song, Hyun-Jeong Ko, Ji Yun Baek, Tuy An Trinh, Christine Beemelmanns, Noriko Yamabe and Ki Hyun Kim

Int. J. Mol. Sci. 2018, 19(9), 2640; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092640 - 06 Sep 2018

Cited by 17 | Viewed by 3637

Abstract

Insect-associated bacteria have been recognized as a very promising natural resource for discovering bioactive secondary metabolites with diverse pharmacological effects. One new isoflavonoid glycoside, termisoflavone D (1), together with seven known isoflavonoids (2–8), were identified from MeOH extracts of the fungus-growing termite-associated Streptomyces sp. RB1. The chemical structure of the new compound 1 was elucidated using comprehensive spectroscopic methods including 1D and 2D NMR, along with LC/MS analysis. The existence of two rhamnose moieties in 1 was determined with comparative NMR analysis, and the absolute configuration was elucidated using chemical reactions. The neuroprotective activities of compounds 1–8 were thoroughly investigated using the murine hippocampal HT22 cell line. Compound 5 prevented glutamate-induced HT22 cell death by blocking intracellular reactive oxygen species (ROS) accumulation. The present study provides the first experimental evidence for the potential use of isoflavonoids from termite-associated bacteria as lead compounds that can prevent neuronal damage induced by glutamate. Full article

(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)

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18 pages, 5202 KiB

Open AccessArticle

Induction of Pro-Apoptotic Endoplasmic Reticulum Stress in Multiple Myeloma Cells by NEO214, Perillyl Alcohol Conjugated to Rolipram

by Thomas C. Chen, Nymph Chan, Shirin Labib, Jiali Yu, Hee-Yeon Cho, Florence M. Hofman and Axel H. Schönthal

Int. J. Mol. Sci. 2018, 19(1), 277; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010277 - 17 Jan 2018

Cited by 9 | Viewed by 4236

Abstract

Despite the introduction of new therapies for multiple myeloma (MM), many patients are still dying from this disease and novel treatments are urgently needed. We have designed a novel hybrid molecule, called NEO214, that was generated by covalent conjugation of the natural monoterpene perillyl alcohol (POH), an inducer of endoplasmic reticulum (ER) stress, to rolipram (Rp), an inhibitor of phosphodiesterase-4 (PDE4). Its potential anticancer effects were investigated in a panel of MM cell lines. We found that NEO214 effectively killed MM cells in vitro with a potency that was over an order of magnitude stronger than that of its individual components, either alone or in combination. The cytotoxic mechanism of NEO214 involved severe ER stress and prolonged induction of CCAAT/enhancer-binding protein homologous protein (CHOP), a key pro-apoptotic component of the ER stress response. These effects were prevented by salubrinal, a pharmacologic inhibitor of ER stress, and by CHOP gene knockout. Conversely, combination of NEO214 with bortezomib, a drug in clinical use for patients with MM, resulted in synergistic enhancement of MM cell death. Combination with the adenylate cyclase stimulant forskolin did not enhance NEO214 impact, indicating that cyclic adenosine 3′,5′-monophosphate (AMP) pathways might play a lesser role. Our study introduces the novel agent NEO214 as a potent inducer of ER stress with significant anti-MM activity in vitro. It should be further investigated as a potential MM therapy aimed at exploiting this tumor’s distinct sensitivity to ER stress. Full article

(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)

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16 pages, 1330 KiB

Open AccessArticle

Mangiferin Accelerates Glycolysis and Enhances Mitochondrial Bioenergetics

by Zhongbo Liu, Pasha Apontes, Ekaterina V. Fomenko, Nan Chi, Victor L. Schuster, Irwin J. Kurland, Jeffrey E. Pessin and Yuling Chi

Int. J. Mol. Sci. 2018, 19(1), 201; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010201 - 09 Jan 2018

Cited by 15 | Viewed by 5920

Abstract

One of the main causes of hyperglycemia is inefficient or impaired glucose utilization by skeletal muscle, which can be exacerbated by chronic high caloric intake. Previously, we identified a natural compound, mangiferin (MGF) that improved glucose utilization in high fat diet (HFD)-induced insulin resistant mice. To further identify the molecular mechanisms of MGF action on glucose metabolism, we conducted targeted metabolomics and transcriptomics studies of glycolyic and mitochondrial bioenergetics pathways in skeletal muscle. These data revealed that MGF increased glycolytic metabolites that were further augmented as glycolysis proceeded from the early to the late steps. Consistent with an MGF-stimulation of glycolytic flux there was a concomitant increase in the expression of enzymes catalyzing glycolysis. MGF also increased important metabolites in the tricarboxylic acid (TCA) cycle, such as α-ketoglutarate and fumarate. Interestingly however, there was a reduction in succinate, a metabolite that also feeds into the electron transport chain to produce energy. MGF increased succinate clearance by enhancing the expression and activity of succinate dehydrogenase, leading to increased ATP production. At the transcriptional level, MGF induced mRNAs of mitochondrial genes and their transcriptional factors. Together, these data suggest that MGF upregulates mitochondrial oxidative capacity that likely drives the acceleration of glycolysis flux. Full article

(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)

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1270 KiB

Open AccessArticle

The Herb–Drug Pharmacokinetic Interaction of 5-Fluorouracil and Its Metabolite 5-Fluoro-5,6-Dihydrouracil with a Traditional Chinese Medicine in Rats

by Ju-Han Liu, Yung-Yi Cheng, Chen-Hsi Hsieh and Tung-Hu Tsai

Int. J. Mol. Sci. 2018, 19(1), 25; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19010025 - 23 Dec 2017

Cited by 8 | Viewed by 6031

Abstract

Background: Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT) is the most common traditional formula given to colorectal and breast cancer patients in Taiwan, according to a statistical study of the National Health Insurance Research Database. 5-Fluorouracil (5-FU) is widely used as the first line of treatment for colorectal cancer. Thus, the aim of study is to investigate the pharmacokinetic interaction of XSLJZT and 5-FU. Methods: To investigate the herb–drug interaction of XSLJZT with 5-FU as well as its metabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) using pharmacokinetics, a high-performance liquid chromatography (HPLC) system coupled with a photodiode array detector was developed to monitor 5-FU and 5-FDHU levels in rat blood. Rats were divided into three cohorts, one of which was administered 5-FU (100 mg/kg, iv—intravenous) alone, while the other two groups were pretreated with low and high doses of XSLJZT (600 mg/kg/day or 2400 mg/kg/day for 5 consecutive days) in combination with 5-FU. Results: The results demonstrated that 5-FU level was not significantly different between the group treated with only 5-FU and the group pretreated with a normal dose of XSLJZT (600 mg/kg/day). However, pharmacokinetic analysis revealed that pretreatment with a high dose of XSLJZT (2400 mg/kg/day) extended the residence time and increased the volume of distribution of 5-FU. No significant distinctions were found in 5-FDHU pharmacokinetic parameters at three doses of XSLJZT. Conclusions: Overall, the pharmacokinetic results confirm the safety of coadministering 5-FU with XSLJZT, and provide practical dosage information for clinical practice. Full article

(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)

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18439 KiB

Open AccessArticle

Fisetin Regulates Nrf2 Expression and the Inflammation-Related Signaling Pathway to Prevent UVB-Induced Skin Damage in Hairless Mice

by Po-Yuan Wu, Jia-Ling Lyu, Yi-Jung Liu, Ting-Yi Chien, Hao-Cheng Hsu, Kuo-Ching Wen and Hsiu-Mei Chiang

Int. J. Mol. Sci. 2017, 18(10), 2118; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18102118 - 10 Oct 2017

Cited by 42 | Viewed by 8425

Abstract

Chronic ultraviolet (UV) exposure may cause skin damage, disrupt skin barrier function, and promote wrinkle formation. UV induces oxidative stress and inflammation, which results in extracellular matrix degradation in the dermis and epidermal hyperplasia. Our previous study demonstrated that fisetin exerts photoprotective activity by inhibiting mitogen-activated protein kinase/activator protein-1/matrix metalloproteinases (MMPs) activation. In this study, fisetin was applied topically to investigate its antiphotodamage effects in hairless mice. The erythema index (a* values) and transepidermal water loss were evaluated to assess skin damage, and immunohistochemical staining was conducted to elucidate the photoprotective mechanism of fisetin. The results revealed that the topical application of fisetin reduced UVB-induced increase in the a* value and wrinkle formation. In addition, fisetin inhibited epidermal hyperplasia and increased the collagen content in the dermis. Fisetin exerted photoprotective activity by inhibiting the expression of MMP-1, MMP-2, and cyclooxygenase-2 and increasing the expression of nuclear factor erythroid 2-related factor. Furthermore, fisetin increased the expression of filaggrin to prevent UVB-induced barrier function disruption. Altogether, the present results provide evidence of the effects and mechanisms of fisetin’s antiphotodamage and antiphotoinflammation activities. Full article

(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)

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11923 KiB

Open AccessArticle

Achiral Mannich-Base Curcumin Analogs Induce Unfolded Protein Response and Mitochondrial Membrane Depolarization in PANC-1 Cells

by Gábor J. Szebeni, Árpád Balázs, Ildikó Madarász, Gábor Pócz, Ferhan Ayaydin, Iván Kanizsai, Roberta Fajka-Boja, Róbert Alföldi, László Hackler Jr. and László G. Puskás

Int. J. Mol. Sci. 2017, 18(10), 2105; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18102105 - 07 Oct 2017

Cited by 33 | Viewed by 6135

Abstract

Achiral Mannich-type curcumin analogs have been synthetized and assayed for their cytotoxic activity. The anti-proliferative and cytotoxic activity of curcuminoids has been tested on human non-small-cell lung carcinoma (A549), hepatocellular carcinoma (HepG2) and pancreatic cancer cell line (PANC-1). Based on the highest anti-proliferative activity nine drug candidates were further tested and proved to cause phosphatidylserine exposure as an early sign of apoptosis. Curcumin analogs with the highest apoptotic activity were selected for mechanistic studies in the most sensitive PANC-1 cells. Cytotoxic activity was accompanied by cytostatic effect since curcumin and analogs treatment led to G₀/G₁ cell cycle arrest. Moreover, cytotoxic effect could be also detected via the accumulation of curcuminoids in the endoplasmic reticulum (ER) and the up-regulation of ER stress-related unfolded protein response (UPR) genes: HSPA5, ATF4, XBP1, and DDIT3. The activated UPR induced mitochondrial membrane depolarization, caspase-3 activation and subsequent DNA breakdown in PANC-1 cells. Achiral curcumin analogs, C509, C521 and C524 possessed superior, 40-times more potent cytotoxic activity compared to natural dihydroxy-dimetoxycurcumin in PANC-1 cells. Full article

(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)

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2680 KiB

Open AccessArticle

Mitochondriotropic and Cardioprotective Effects of Triphenylphosphonium-Conjugated Derivatives of the Diterpenoid Isosteviol

by Lara Testai, Irina Strobykina, Victor V. Semenov, Marina Semenova, Eleonora Da Pozzo, Alma Martelli, Valentina Citi, Claudia Martini, Maria C. Breschi, Vladimir E. Kataev and Vincenzo Calderone

Int. J. Mol. Sci. 2017, 18(10), 2060; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18102060 - 26 Sep 2017

Cited by 24 | Viewed by 4499

Abstract

Mitochondria play a crucial role in the cell fate; in particular, reducing the accumulation of calcium in the mitochondrial matrix offers cardioprotection. This affect is achieved by a mild depolarization of the mitochondrial membrane potential, which prevents the assembly and opening of the mitochondrial permeability transition pore. For this reason, mitochondria are an attractive target for pharmacological interventions that prevent ischaemia/reperfusion injury. Isosteviol is a diterpenoid created from the acid hydrolysis of Stevia rebaudiana Bertoni (fam. Asteraceae) glycosides that has shown protective effects against ischaemia/reperfusion injury, which are likely mediated through the activation of mitochondrial adenosine tri-phosphate (ATP)-sensitive potassium (mitoKATP) channels. Some triphenylphosphonium (triPP)-conjugated derivatives of isosteviol have been developed, and to evaluate the possible pharmacological benefits that result from these synthetic modifications, in this study, the mitochondriotropic properties of isosteviol and several triPP-conjugates were investigated in rat cardiac mitochondria and in the rat heart cell line H9c2. This study’s main findings highlight the ability of isosteviol to depolarize the mitochondrial membrane potential and reduce calcium uptake by the mitochondria, which are typical functions of mitochondrial potassium channel openings. Moreover, triPP-conjugated derivatives showed a similar behavior to isosteviol but at lower concentrations, indicative of their improved uptake into the mitochondrial matrix. Finally, the cardioprotective property of a selected triPP-conjugated derivative was demonstrated in an in vivo model of acute myocardial infarct. Full article

(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)

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5481 KiB

Open AccessArticle

Self-Nanoemulsifying Drug Delivery System for Resveratrol: Enhanced Oral Bioavailability and Reduced Physical Fatigue in Rats

by Ching-Chi Yen, Chih-Wei Chang, Mei-Chich Hsu and Yu-Tse Wu

Int. J. Mol. Sci. 2017, 18(9), 1853; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18091853 - 25 Aug 2017

Cited by 52 | Viewed by 5839

Abstract

Resveratrol (RES), a natural polyphenolic compound, exerts anti-fatigue activity, but its administration is complicated by its low water solubility. To improve RES bioavailability, this study developed a self-nanoemulsifying drug delivery system (SNEDDS) for RES and evaluated its anti-fatigue activity and rat exercise performance by measuring fatigue-related parameters, namely lactate, ammonia, plasma creatinine phosphokinase, and glucose levels and the swimming time to exhaustion. Through solubility and emulsification testing, the optimized SNEDDS composed of Capryol 90, Cremophor EL, and Tween 20 was developed; the average particle size in this formulation, which had favorable self-emulsification ability, was approximately 41.3 ± 4.1 nm. Pharmacokinetic studies revealed that the oral bioavailability of the optimized RES-SNEDDS increased by 3.2-fold compared with that of the unformulated RES-solution. Pretreatment using the RES-SNEDDS before exercise accelerated the recovery of lactate after exercise; compared with the vehicle group, the plasma ammonia level in the RES-SNEDDS group significantly decreased by 65.4%, whereas the glucose level significantly increased by approximately 1.8-fold. Moreover, the swimming time to exhaustion increased by 2.1- and 1.8-fold, respectively, compared with the vehicle and RES-solution pretreatment groups. Therefore, the developed RES-SNEDDS not only enhances the oral bioavailability of RES but may also exert anti-fatigue pharmacological effect. Full article

(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)

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Review

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31 pages, 5176 KiB

Open AccessReview

Antiproliferative Effects of Alkaloid Evodiamine and Its Derivatives

by Xu Hu, Dahong Li, Chun Chu, Xu Li, Xianhua Wang, Ying Jia, Huiming Hua and Fanxing Xu

Int. J. Mol. Sci. 2018, 19(11), 3403; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113403 - 30 Oct 2018

Cited by 46 | Viewed by 4467

Abstract

Alkaloids, a category of natural products with ring structures and nitrogen atoms, include most U.S. Food and Drug Administration approved plant derived anti-cancer agents. Evodiamine is an alkaloid with attractive multitargeting antiproliferative activity. Its high content in the natural source ensures its adequate supply on the market and guarantees further medicinal study. To the best of our knowledge, there is no systematic review about the antiproliferative effects of evodiamine derivatives. Therefore, in this article the review of the antiproliferative activities of evodiamine will be updated. More importantly, the antiproliferative activities of structurally modified new analogues of evodiamine will be summarized for the first time. Full article

(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)

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22 pages, 1725 KiB

Open AccessReview

Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety

by Rute Moreira, David M. Pereira, Patrícia Valentão and Paula B. Andrade

Int. J. Mol. Sci. 2018, 19(6), 1668; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19061668 - 05 Jun 2018

Cited by 181 | Viewed by 12173

Abstract

Pyrrolizidine alkaloids (PA) are widely distributed in plants throughout the world, frequently in species relevant for human consumption. Apart from the toxicity that these molecules can cause in humans and livestock, PA are also known for their wide range of pharmacological properties, which can be exploited in drug discovery programs. In this work we review the current body of knowledge regarding the chemistry, toxicology, pharmacology and food safety of PA. Full article

(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)

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