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Natural Organic Substances as Starting Bricks for the Semi-synthesis of New Compounds

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 15843

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Special Issue Editor

Dr. Claudio Frezza

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Guest Editor

Department of Environmental Biology, University of Rome, La Sapienza, Rome, Italy
Interests: HPLC and NMR analysis; phytochemistry; synthesis of natural products; chemotaxonomy; ethnopharmacology; nutraceutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The concept of using natural products as starting bases for the semi-synthesis of new compounds has become a common practice by now. Moreover, it has proven to be an important and interesting tool in order to remedy two specific limitations often associated to natural products, i.e., their little recovery percentages from their natural sources, plants, and so on and their little pharmacological effects due to general, pharmacokinetic, and pharmacodynamic problems. The main and probably most well known example in the former context is surely that of taxol. In fact, the ultimate decision to obtain it after a semi-synthesis process from 10-deacetylbaccatin III has really made history. Indeed, this Special Issue wants to better develop the latter scenario. In particular, it wants to highlight how often a simple and safe semi-synthetic procedure can greatly increase the potential of some natural organic compounds as pharmacologically active substances unlike if they were used as recovered from their natural sources. The typical example of this is linked to salicylic acid and acetyl-salicylic acid. No restrictions about the kind of compounds and the pharmacological effects studied are given, but the differences in the pharmacological activity between the natural compound and its semi-synthetic derivative or derivatives must be showed and explained.

Dr. Claudio Frezza
Guest Editor

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Keywords

Natural products
Plant sources
Isolation
Semi-synthesis
Active substances
Pharmacology

Related Special Issue

Natural Organic Substances as Starting Bricks for the Semi-synthesis of New Compounds II in Molecules (1 article)

Published Papers (6 papers)

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Research

12 pages, 2176 KiB

Open AccessArticle

Semi-Synthesis and In Vitro Anti-Cancer Evaluation of Magnolol Derivatives

by Xiao-Long Sun, Mei-Lin Zhu, Yi-Qun Dai, Hong-Mei Li, Bo-Han Li, Hui Ma, Chang-Hao Zhang and Cheng-Zhu Wu

Molecules 2021, 26(14), 4302; https://doi.org/10.3390/molecules26144302 - 15 Jul 2021

Cited by 8 | Viewed by 2226

Abstract

Magnolol (MAG), a biphenolic neolignan, has various biological activities including antitumor effects. In this study, 15 MAG derivatives were semi-synthesized and evaluated for their in vitro anticancer activities. From these derivatives, compound 6a exhibited the best cytotoxic activity against four human cancer cell lines, with IC₅₀ values ranging from 20.43 to 28.27 μM. Wound-healing and transwell assays showed that compound 6a significantly inhibited the migration and invasion of MDA-MB-231 cells. In addition, Western blotting experiments, performed using various concentrations of 6a, demonstrated that it downregulates the expression of HIF-1α, MMP-2, and MMP-9 in a concentration-dependent manner. Overall, these results suggest that substituting a benzyl group having F atoms substituted at the C2 position on MAG is a viable strategy for the structural optimization of MAG derivatives as anticancer agents. Full article

(This article belongs to the Special Issue Natural Organic Substances as Starting Bricks for the Semi-synthesis of New Compounds)

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15 pages, 20853 KiB

Open AccessArticle

Induction of Apoptosis and Regulation of MicroRNA Expression by (2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) Treatment on MCF-7 Breast Cancer Cells

by Swee Keong Yeap, Norlaily Mohd Ali, Muhammad Nadeem Akhtar, Nursyamirah Abd Razak, Zhi Xiong Chong, Wan Yong Ho, Lily Boo, Seema Zareen, Tonni Agustiono Kurniawan, Ram Avtar, Stephanie Y. L. Ng, Alan Han Kiat Ong and Noorjahan Banu Alitheen

Molecules 2021, 26(5), 1277; https://doi.org/10.3390/molecules26051277 - 26 Feb 2021

Cited by 9 | Viewed by 3097

Abstract

(2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) is a synthetic curcumin analogue, which has been reported to possess anti-tumor, anti-metastatic, and anti-invasion properties on estrogen receptor (ER) negative breast cancer cells in vitro and in vivo. However, the cytotoxic effects of BHMC on ER positive breast cancer cells were not widely reported. This study was aimed to investigate the cytotoxic potential of BHMC on MCF-7 cells using cell viability, cell cycle, and apoptotic assays. Besides, microarray and quantitative polymerase chain reaction (qPCR) were performed to identify the list of miRNAs and genes, which could be dysregulated following BHMC treatment. The current study discovered that BHMC exhibits selective cytotoxic effects on ER positive MCF-7 cells as compared to ER negative MDA-MB-231 cells and normal breast cells, MCF-10A. BHMC was shown to promote G2/M cell cycle arrest and apoptosis in MCF-7 cells. Microarray and qPCR analysis demonstrated that BHMC treatment would upregulate several miRNAs like miR-3195 and miR-30a-3p and downregulate miRNAs such as miR-6813-5p and miR-6132 in MCF-7 cells. Besides, BHMC administration was also found to downregulate few tumor-promoting genes like VEGF and SNAIL in MCF-7. In conclusion, BHMC induced apoptosis in the MCF-7 cells by altering the expressions of apoptotic-regulating miRNAs and associated genes. Full article

(This article belongs to the Special Issue Natural Organic Substances as Starting Bricks for the Semi-synthesis of New Compounds)

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15 pages, 4309 KiB

Open AccessArticle

A Facile Semisynthesis and Evaluation of Garcinoic Acid and Its Analogs for the Inhibition of Human DNA Polymerase β

by Satheesh Gujarathi, Maroof Khan Zafar, Xingui Liu, Robert L. Eoff and Guangrong Zheng

Molecules 2020, 25(24), 5847; https://doi.org/10.3390/molecules25245847 - 11 Dec 2020

Cited by 2 | Viewed by 2298

Abstract

Garcinoic acid has been identified as an inhibitor of DNA polymerase β (pol β). However, no structure-activity relationship (SAR) studies of garcinoic acid as a pol β inhibitor have been conducted, in part due to the lack of an efficient synthetic method for this natural product and its analogs. We developed an efficient semi-synthetic method for garcinoic acid and its analogs by starting from natural product δ-tocotrienol. Our preliminary SAR studies provided a valuable insight into future discovery of garcinoic acid-based pol β inhibitors. Full article

(This article belongs to the Special Issue Natural Organic Substances as Starting Bricks for the Semi-synthesis of New Compounds)

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17 pages, 1819 KiB

Open AccessArticle

Oleuropein Aglycone Peracetylated (3,4-DHPEA-EA(P)) Attenuates H₂O₂-Mediated Cytotoxicity in C2C12 Myocytes via Inactivation of p-JNK/p-c-Jun Signaling Pathway

by Monica Nardi, Sara Baldelli, Maria Rosa Ciriolo, Paola Costanzo, Antonio Procopio and Carmela Colica

Molecules 2020, 25(22), 5472; https://doi.org/10.3390/molecules25225472 - 23 Nov 2020

Cited by 4 | Viewed by 2148

Abstract

Oleuropein, a glycosylated secoiridoid present in olive leaves, is known to be an important antioxidant phenolic compound. We studied the antioxidant effect of low doses of oleuropein aglycone (3,4-DHPEA-EA) and oleuropein aglycone peracetylated (3,4-DHPEA-EA(P)) in murine C2C12 myocytes treated with hydrogen peroxide (H₂O₂). Both compounds were used at a concentration of 10 μM and were able to inhibit cell death induced by the H₂O₂ treatment, with 3,4-DHPEA-EA(P) being more. Under our experimental conditions, H₂O₂ efficiently induced the phosphorylated-active form of JNK and of its downstream target c-Jun. We demonstrated, by Western blot analysis, that 3,4-DHPEA-EA(P) was efficient in inhibiting the phospho-active form of JNK. This data suggests that the growth arrest and cell death of C2C12 proceeds via the JNK/c-Jun pathway. Moreover, we demonstrated that 3,4-DHPEA-EA(P) affects the myogenesis of C2C12 cells; because MyoD mRNA levels and the differentiation process are restored with 3,4-DHPEA-EA(P) after treatment. Overall, the results indicate that 3,4-DHPEA-EA(P) prevents ROS-mediated degenerative process by functioning as an efficient antioxidant. Full article

(This article belongs to the Special Issue Natural Organic Substances as Starting Bricks for the Semi-synthesis of New Compounds)

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18 pages, 1347 KiB

Open AccessArticle

Semisynthetic Cardenolides Acting as Antiviral Inhibitors of Influenza A Virus Replication by Preventing Polymerase Complex Formation

by Laurita Boff, André Schreiber, Aline da Rocha Matos, Juliana Del Sarto, Linda Brunotte, Jennifer Munkert, Flaviano Melo Ottoni, Gabriela Silva Ramos, Wolfgang Kreis, Fernão Castro Braga, Ricardo José Alves, Rodrigo Maia de Pádua, Cláudia Maria Oliveira Simões and Stephan Ludwig

Molecules 2020, 25(20), 4853; https://doi.org/10.3390/molecules25204853 - 21 Oct 2020

Cited by 2 | Viewed by 2476

Abstract

Influenza virus infections represent a major public health issue by causing annual epidemics and occasional pandemics that affect thousands of people worldwide. Vaccination is the main prophylaxis to prevent these epidemics/pandemics, although the effectiveness of licensed vaccines is rather limited due to the constant mutations of influenza virus antigenic characteristics. The available anti-influenza drugs are still restricted and there is an increasing viral resistance to these compounds, thus highlighting the need for research and development of new antiviral drugs. In this work, two semisynthetic derivatives of digitoxigenin, namely C10 (3β-((N-(2-hydroxyethyl)aminoacetyl)amino-3-deoxydigitoxigenin) and C11 (3β-(hydroxyacetyl)amino-3-deoxydigitoxigenin), showed anti-influenza A virus activity by affecting the expression of viral proteins at the early and late stages of replication cycle, and altering the transcription and synthesis of new viral proteins, thereby inhibiting the formation of new virions. Such antiviral action occurred due to the interference in the assembly of viral polymerase, resulting in an impaired polymerase activity and, therefore, reducing viral replication. Confirming the in vitro results, a clinically relevant ex vivo model of influenza virus infection of human tumor-free lung tissues corroborated the potential of these compounds, especially C10, to completely abrogate influenza A virus replication at the highest concentration tested (2.0 µM). Taken together, these promising results demonstrated that C10 and C11 can be considered as potential new anti-influenza drug candidates. Full article

(This article belongs to the Special Issue Natural Organic Substances as Starting Bricks for the Semi-synthesis of New Compounds)

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9 pages, 1528 KiB

Open AccessArticle

Semi-Synthesis of C-Ring Cyclopropyl Analogues of Fraxinellone and Their Insecticidal Activity Against Mythimna separata Walker

by Xiao-Jun Yang, Qing-Miao Dong, Min-Ran Wang and Jiang-Jiang Tang

Molecules 2020, 25(5), 1109; https://doi.org/10.3390/molecules25051109 - 02 Mar 2020

Cited by 6 | Viewed by 2797

Abstract

Fraxinellone (1) is a naturally occurring degraded limonoid isolated from Meliaceae and Rutaceae plants. As a potential natural-product-based insecticidal agent, fraxinellone has been structurally modified to improve its activity. Furan ring of fraxinellone is critical in exhibiting its insecticidal activity, but with few modifications. Herein, C-ring-modified cyclopropyl analogues were semi-synthesized by Rh(II)-catalyzed cyclopropanation. The structures of the target compounds were well characterized by NMR and HRMS. The precise three-dimensional structural information of 3a was established by X-ray crystallography. Their insecticidal activity was evaluated against Mythimna separata Walker by a leaf-dipping method. Compound 3c exhibited stronger insecticidal activity than 1 and toosendanin against M. separata with teratogenic symptoms during the different periods, implying that cyclopropanation of the furan ring could strengthen the insecticidal activity of fraxinellone. Full article

(This article belongs to the Special Issue Natural Organic Substances as Starting Bricks for the Semi-synthesis of New Compounds)

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