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12 pages, 1450 KiB

Open AccessArticle

Synthetic Study toward Triterpenes from the Schisandraceae Family of Natural Products

by Pavle Kravljanac and Edward A. Anderson

Molecules 2023, 28(11), 4468; https://doi.org/10.3390/molecules28114468 - 31 May 2023

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Triterpenoid natural products from the Schisandraceae family have long presented a significant synthetic challenge. Lancifodilactone I, a member of the family not previously synthesized, was identified as a key natural product target, from which many other members could be synthesized. We envisaged that [...] Read more.

Triterpenoid natural products from the Schisandraceae family have long presented a significant synthetic challenge. Lancifodilactone I, a member of the family not previously synthesized, was identified as a key natural product target, from which many other members could be synthesized. We envisaged that the core ring system of lancifodilactone I could be accessed by a strategy involving palladium-catalysed cascade cyclisation of a bromoenynamide, via carbopalladation, Suzuki coupling and 8π-electrocyclisation, to synthesize the core 7,8-fused ring system. Exploration of this strategy on model systems resulted in efficient syntheses of 5,6- and 5,8-fused systems in high yields, which represent the first such cyclisation where the ynamide nitrogen atom is ‘external’ to the forming ring system. The enamide functionality resident in the cascade cyclisation product was found to be less nucleophilic than the accompanying tri-/tetrasubstituted alkene(s), enabling regioselective oxidations. Application of this strategy to 7,6-, and 7,8-fused systems, and ultimately the ‘real’ substrate, was ultimately thwarted by the difficulty of 7-membered ring closure, leading to side product formation. Nevertheless, a tandem bromoenynamide carbopalladation, Suzuki coupling and 6/8π-electrocyclisation was shown to be a highly efficient tactic for the formation of bicyclic enamides, which may find applications in other synthetic contexts. Full article

(This article belongs to the Special Issue Natural Compounds and New Analogs in Chemical Synthesis: A Themed Issue in Honor of Professor Dr. Mark Moloney)

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15 pages, 3342 KiB

Open AccessFeature PaperArticle

An Enantiospecific Synthesis of 5-epi-α-Bulnesene

by Jiarui Zong and Jeremy Robertson

Molecules 2023, 28(9), 3900; https://doi.org/10.3390/molecules28093900 - 05 May 2023

Cited by 1 | Viewed by 1254

Abstract

As a result of its unique fragrance and wider role in traditional medicine, agarwood produced in Aquilaria spp. and certain other trees has been harvested to near extinction as a natural phenomenon. Artificially induced agarwood production in Aquilaria plantations has sated some of [...] Read more.

As a result of its unique fragrance and wider role in traditional medicine, agarwood produced in Aquilaria spp. and certain other trees has been harvested to near extinction as a natural phenomenon. Artificially induced agarwood production in Aquilaria plantations has sated some of the demand although the product quality is variable. Synthetic chemistry may have a role to play in providing sustainable routes to many of the fragrant components identified in agarwood and its smoke when burnt as incense. In this work, we report efforts towards a total synthesis of the guaiane sesquiterpene α-bulnesene, which is found, along with its more fragrant oxidised derivatives, in agarwood. Following the ring-expansion of (R)-carvone using reported procedures, α-butenylation gave a substrate for samarium diiodide mediated reductive cyclisation, the two butenyl epimers of the substrate each leading to a single bicyclic alcohol (24 and 25). Overall homoconjugate hydride reduction of one of these alcohols was achieved by Lewis acid-mediated ionisation and then hydride transfer from triethylsilane to complete an overall seven-step synthesis of 5-epi-α-bulnesene. This new synthesis paves the way for short routes to both α-bulnesene enantiomers and a study of their aerial and enzymatic oxidation products. Full article

(This article belongs to the Special Issue Natural Compounds and New Analogs in Chemical Synthesis: A Themed Issue in Honor of Professor Dr. Mark Moloney)

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19 pages, 3786 KiB

Open AccessArticle

Novel Tetrahydro-[1,2,4]triazolo[3,4-a]isoquinoline Chalcones Suppress Breast Carcinoma through Cell Cycle Arrests and Apoptosis

by Mahmoud I. M. Darwish, Ahmed M. Moustafa, Asmaa M. Youssef, Mohamed Mansour, Ahmed I. Yousef, Abdelfatteh El Omri, Hossam H. Shawki, Magda F. Mohamed, Hamdi M. Hassaneen, Ismail A. Abdelhamid and Hisashi Oishi

Molecules 2023, 28(8), 3338; https://doi.org/10.3390/molecules28083338 - 10 Apr 2023

Cited by 6 | Viewed by 2194

Abstract

Chalcones are interesting anticancer drug candidates which have attracted much interest due to their unique structure and their extensive biological activity. Various functional modifications in chalcones have been reported, along with their pharmacological properties. In the current study, novel chalcone derivatives with the [...] Read more.

Chalcones are interesting anticancer drug candidates which have attracted much interest due to their unique structure and their extensive biological activity. Various functional modifications in chalcones have been reported, along with their pharmacological properties. In the current study, novel chalcone derivatives with the chemical base of tetrahydro-[1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-arylprop-2-en-1-one were synthesized, and the structure of their molecules was confirmed through NMR spectroscopy. The antitumor activity of these newly synthesized chalcone derivatives was tested on mouse (Luc-4T1) and human (MDA-MB-231) breast cancer cell lines. The antiproliferative effect was evaluated through SRB screening and the MTT assay after 48 h of treatment at different concentrations. Interestingly, among the tested chalcone derivatives, chalcone analogues with a methoxy group were found to have significant anticancer activity and displayed gradient-dependent inhibition against breast cancer cell proliferation. The anticancer properties of these unique analogues were examined further by cytometric analysis of the cell cycle, quantitative PCR, and the caspases-Glo 3/7 assay. Chalcone methoxy derivatives showed the capability of cell cycle arrest and increased Bax/Bcl2 mRNA ratios as well as caspases 3/7 activity. The molecular docking analysis suggests that these chalcone methoxy derivatives may inhibit anti-apoptotic proteins, particularly cIAP1, BCL2, and EGFRK proteins. In conclusion, our findings confirm that chalcone methoxy derivatives could be considered to be potent drug candidates against breast cancer. Full article

(This article belongs to the Special Issue Natural Compounds and New Analogs in Chemical Synthesis: A Themed Issue in Honor of Professor Dr. Mark Moloney)

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13 pages, 2902 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Sclareolide-Indole Conjugates and Their Derivatives

by Ying Cheng, Xilin Lyu, Chen Liu, Xiancheng Wang, Jing Cheng, Daizhou Zhang, Xiangjing Meng and Yujun Zhao

Molecules 2023, 28(4), 1737; https://doi.org/10.3390/molecules28041737 - 11 Feb 2023

Cited by 1 | Viewed by 1676

Abstract

Sclareolide is a sesquiterpene lactone isolated from various plant sources in tons every year and is commercially used as a flavor ingredient in the cosmetic and food industries. Antitumor and antiviral activities of sclareolide have been previously reported. However, biological studies of sclareolide [...] Read more.

Sclareolide is a sesquiterpene lactone isolated from various plant sources in tons every year and is commercially used as a flavor ingredient in the cosmetic and food industries. Antitumor and antiviral activities of sclareolide have been previously reported. However, biological studies of sclareolide synthetic analogous are few. In view of these, we developed a robust synthetic method that allows the assembly of 36 novel sclareolide-indole conjugates and their derivatives. The synthetic method was based on TiCl₄-promoted nucleophilic substitution of sclareolide-derived hemiacetal 4, while electron-rich aryles including indoles, polyphenol ethers, and pyrazolo [1,5-a]pyridine were good substrates. The stereochemistry of the final products was confirmed by single-crystal X-ray diffraction analysis, while the antiproliferative activities of selected final products were tested in K562 and MV4-11 cancer cell lines. Cytometric flow analysis shows that lead compounds 8k- and 10-induced robust apoptosis in MV4-11 cancer cells, while they exhibited weak impact on cell cycle progression. Taken together, our study suggests that sclareolide could be a good template and substrate for the synthesis of novel antiproliferative compounds. Full article

(This article belongs to the Special Issue Natural Compounds and New Analogs in Chemical Synthesis: A Themed Issue in Honor of Professor Dr. Mark Moloney)

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11 pages, 1132 KiB

Open AccessArticle

Chloroquine-Based Mitochondrial ATP Inhibitors

by Zhiguo Wang, Robert J. Sheaff and Syed R. Hussaini

Molecules 2023, 28(3), 1161; https://doi.org/10.3390/molecules28031161 - 24 Jan 2023

Viewed by 1611

Abstract

Mitochondria is an important drug target for ailments ranging from neoplastic to neurodegenerative diseases and metabolic diseases. Here, we describe the synthesis of chloroquine analogs and show the results of mitochondrial ATP inhibition testing. The 2,4-dinitrobenzene-based analogs showed concentration-dependent mitochondrial (mito.) ATP inhibition. [...] Read more.

Mitochondria is an important drug target for ailments ranging from neoplastic to neurodegenerative diseases and metabolic diseases. Here, we describe the synthesis of chloroquine analogs and show the results of mitochondrial ATP inhibition testing. The 2,4-dinitrobenzene-based analogs showed concentration-dependent mitochondrial (mito.) ATP inhibition. The most potent mito. ATP inhibitor was found to be N-(4-((2,4-Dinitrophenyl)amino)pentyl)-N-ethylacetamide (17). Full article

(This article belongs to the Special Issue Natural Compounds and New Analogs in Chemical Synthesis: A Themed Issue in Honor of Professor Dr. Mark Moloney)

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11 pages, 2083 KiB

Open AccessArticle

Semisynthesis and Pesticidal Activities of Novel Cholesterol Ester Derivatives Containing Cinnamic Acid-like Fragments

by Rongfei Lu, Jianwei Xu, Zhen Wang, Shaoyong Zhang, Hailong Wang, Hui Xu and Min Lv

Molecules 2022, 27(23), 8437; https://doi.org/10.3390/molecules27238437 - 02 Dec 2022

Cited by 1 | Viewed by 1267

Abstract

Due to the extensive use of agrochemicals resulting in the emergence of pesticide resistance and ecological environment problems, the research and development of new alternatives for crop protection is highly desirable. In order to discover potent natural product-based insecticide candidates, a series of [...] Read more.

Due to the extensive use of agrochemicals resulting in the emergence of pesticide resistance and ecological environment problems, the research and development of new alternatives for crop protection is highly desirable. In order to discover potent natural product-based insecticide candidates, a series of new cholesterol ester derivatives containing cinnamic acid-like fragments at the C-7 position were synthesized. Some derivatives showed potent pesticidal activities. Against Mythimna separata Walker, compounds 2a, Id, Ig, and IIg showed 2.1–2.4-fold growth-inhibitory activity of the precursor cholesterol. Against Plutella xylostella Linnaeus, compounds Ig, IIf, and IIi exhibited 1.9–2.1-fold insecticidal activity of cholesterol. These results will pave the way for the future synthesis of cholesterol-based derivatives as agrochemicals. Full article

(This article belongs to the Special Issue Natural Compounds and New Analogs in Chemical Synthesis: A Themed Issue in Honor of Professor Dr. Mark Moloney)

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17 pages, 2454 KiB

Open AccessFeature PaperArticle

Synthesis, In Silico and In Vivo Toxicity Assessment of Functionalized Pyridophenanthridinones via Sequential MW-Assisted Intramolecular Friedel-Crafts Alkylation and Direct C–H Arylation

by Marlyn C. Ortiz Villamizar, Carlos E. Puerto Galvis, Silvia A. Pedraza Rodríguez, Fedor I. Zubkov and Vladimir V. Kouznetsov

Molecules 2022, 27(23), 8112; https://doi.org/10.3390/molecules27238112 - 22 Nov 2022

Cited by 2 | Viewed by 1116

Abstract

A rapid, efficient, and original synthesis of novel pyrido[3,2,1-de]phenanthridin-6-ones is reported. First, the key cinnamamide intermediates 8a–f were easily prepared from commercial substituted anilines, cinnamic acid, and 2-bromobenzylbromide in a tandem amidation and N-alkylation protocol. Then, these N [...] Read more.

A rapid, efficient, and original synthesis of novel pyrido[3,2,1-de]phenanthridin-6-ones is reported. First, the key cinnamamide intermediates 8a–f were easily prepared from commercial substituted anilines, cinnamic acid, and 2-bromobenzylbromide in a tandem amidation and N-alkylation protocol. Then, these N-aryl-N-(2-bromobenzyl) cinnamamides 8a–f were subjected to a TFA-mediated intramolecular Friedel-Crafts alkylation followed by a Pd-catalyzed direct C–H arylation to obtain a series of potentially bioactive 4-phenyl-4,5-dihydro-6H,8H-pyrido[3,2,1-de]phenanthridin-6-one derivatives 4a–f in good yields. Finally, the toxicological profile of the prepared final compounds, including their corresponding intermediates, was explored through in silico computational methods, while the acute toxicity toward zebrafish embryos (96 hpf-LC₅₀, 50% lethal concentration) was also determined in the present study. Full article

(This article belongs to the Special Issue Natural Compounds and New Analogs in Chemical Synthesis: A Themed Issue in Honor of Professor Dr. Mark Moloney)

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Review

Jump to: Research

19 pages, 8725 KiB

Open AccessReview

Actin-Interacting Amphidinolides: Syntheses and Mechanisms of Action of Amphidinolides X, J, and K

by Anna M. Costa

Molecules 2023, 28(13), 5249; https://doi.org/10.3390/molecules28135249 - 06 Jul 2023

Cited by 1 | Viewed by 900

Abstract

Amphidinolides are a family of more than forty macrolides of varying sizes and complex structures isolated from dinoflagellates of the genus Amphidinium. Although all of them display potent-to-moderate cytotoxicity, their full bioactivity profile and mode of action have not been fully investigated. [...] Read more.

Amphidinolides are a family of more than forty macrolides of varying sizes and complex structures isolated from dinoflagellates of the genus Amphidinium. Although all of them display potent-to-moderate cytotoxicity, their full bioactivity profile and mode of action have not been fully investigated. Access to enough material is needed for these studies, but samples of these compounds are limited due to the minute amounts that can only be obtained by either large-scale cultivation of the organism that produces them or by total synthesis. Of all the amphidinolides known to date, only the targets of five of them (B1, H1, J, K, and X) have been examined and all have been found to interact with actin, a crucial cytoskeletal protein. This paper reviews what is currently known about actin-interacting amphidinolides, with a focus on the research of our group. Amphidinolides J and X are F-actin destabilizers, whereas Amphidinolides H1 and K stabilize actin filaments, likely via different mechanisms. More precise details of the interaction between amphidinolides and actin are missing. Full article

(This article belongs to the Special Issue Natural Compounds and New Analogs in Chemical Synthesis: A Themed Issue in Honor of Professor Dr. Mark Moloney)

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