Leucettamine B analogs and their carborane derivative as potential anti-cancer agents: Design, synthesis, and biological evaluation

Hsu, Ming Hua; Hsieh, Cheng Ying; Kapoor, Mohit; Chang, Jui Hsun; Chu, Hsueh Liang; Cheng, Tsai Mu; Hsu, Kai Cheng; Lin, Tony Eight; Tsai, Fu-Yuan; Horng, Jia Cherng

doi:10.1016/j.bioorg.2020.103729

Cited by 13 publications

(10 citation statements)

References 64 publications

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“…In addition, lots of marine-derived compounds have widely shown anticancer abilities, such as philinopside A isolated from the sea cucumber [125], a copper coordination compound ZZF51 isolated from a marine fungus [126], leucettamol A from the marine sponge [127], pyrroloazepinone and indoloazepinone from marine natural products [128], bastadins-6, -9 and -16 isolated from the marine sponge [129], α-pyrone derivatives from marine actinomycete Streptomyces [130], fascaplysin from marine sponges [131], extracts of two different starfish species [132], leucettamine B from marine sponge [133], crude venom from jellyfish [134] and lamellarin D and its derivatives from marine products [135].…”

Section: Potential Marine-derived Anticancer Drugsmentioning

confidence: 99%

Development of Marine-Derived Compounds for Cancer Therapy

Zuo

Kwok

2021

Marine Drugs

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Cancer has always been a threat to human health with its high morbidity and mortality rates. Traditional therapy, including surgery, chemotherapy and radiotherapy, plays a key role in cancer treatment. However, it is not able to prevent tumor recurrence, drug resistance and treatment side effects, which makes it a very attractive challenge to search for new effective and specific anticancer drugs. Nature is a valuable source of multiple pharmaceuticals, and most of the anticancer drugs are natural products or derived from them. Marine-derived compounds, such as nucleotides, proteins, peptides and amides, have also shed light on cancer therapy, and they are receiving a fast-growing interest due to their bioactive properties. Their mechanisms contain anti-angiogenic, anti-proliferative and anti-metastasis activities; cell cycle arrest; and induction of apoptosis. This review provides an overview on the development of marine-derived compounds with anticancer properties, both their applications and mechanisms, and discovered technologies.

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Section: Potential Marine-derived Anticancer Drugsmentioning

confidence: 99%

Development of Marine-Derived Compounds for Cancer Therapy

Zuo

Kwok

2021

Marine Drugs

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“…Heterocycles containing oxygen and nitrogen as reactive and biomimetic pharmacophores have a potent impact in the domain of medicinal chemistry [5] . In particular, five‐ or six‐membered heterocycles and their derivatives play critical roles in various drugs and natural molecules [6] . For example, barbituric acid and its derivatives have drawn much attention from pharmacologists because of their extensive biological properties including anti‐inflammatory, antibacterial and anticancer activities [7–10] .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Anticancer Activity of Cinnamoylated Barbituric Acid Derivatives

Liu

et al. 2022

Chemistry & Biodiversity

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This work deals with the design and synthesis of 18 barbituric acid derivatives bearing 1,3‐dimethylbarbituric acid and cinnamic acid scaffolds to find potent anticancer agents. The target molecules were obtained through Knoevenagel condensation and acylation reaction. The cytotoxicity was assessed by the MTT assay. Flowcytometry was performed to determine the cell cycle arrest, apoptosis, ROS levels and the loss of MMP. The ratios of GSH/GSSG and the MDA levels were determined by using UV spectrophotometry. The results revealed that introducing substitutions (CF3, OCF3, F) on the meta‐ of the benzyl ring of barbituric acid derivatives led to a considerable increase in the antiproliferative activities compared with that of corresponding ortho‐ and para‐substituted barbituric acid derivatives. Mechanism investigation implied that the 1c could increase the ROS and MDA level, decrease the ratio of GSH/GSSG and MMP, and lead to cell cycle arrest. Further research is needed for structural optimization to enhance hydrophilicity, thereby improve the biological activity of these compounds.

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“…Several analogs of its family such as aplysinopsine and clathridine are medicinally active molecules that have applications in many pharmaceuticals and healthcare products. A recent study also reported the potential anticancer activity of a series of Leucettamine B synthesized derivatives [ 33 ]. However, leucettamine B and its analog leucettine L41 have not been well studied for their kinase inhibitory activity.…”

Section: Introductionmentioning

confidence: 99%

Development of New Meridianin/Leucettine-Derived Hybrid Small Molecules as Nanomolar Multi-Kinase Inhibitors with Antitumor Activity

et al. 2021

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Although the sea ecosystem offers a broad range of bioactivities including anticancer, none of the FDA-approved antiproliferative protein kinase inhibitors are derived from a marine source. In a step to develop new marine-inspired potent kinase inhibitors with antiproliferative activities, a new series of hybrid small molecules (5a–5g) was designed and synthesized based on chemical moieties derived from two marine natural products (Meridianin E and Leucettamine B). Over a panel of 14 cancer-related kinases, a single dose of 10 µM of the parent hybrid 5a possessing the benzo[d][1,3]dioxole moiety of Leucettamine B was able to inhibit the activity of FMS, LCK, LYN, and DAPK1 kinases with 82.5 ± 0.6, 81.4 ± 0.6, 75.2 ± 0.0, and 55 ± 1.1%, respectively. Further optimization revealed the most potent multiple kinase inhibitor of this new series (5g) with IC50 values of 110, 87.7, and 169 nM against FMS, LCK, and LYN kinases, respectively. Compared to imatinib (FDA-approved multiple kinase inhibitor), compound 5g was found to be ~ 9- and 2-fold more potent than imatinib over both FMS and LCK kinases, respectively. In silico docking simulation models of the synthesized compounds within the active site of FMS, LCK, LYN, and DAPK1 kinases offered reasonable explanations of the elicited biological activities. In an in vitro anticancer assay using a library of 60 cancer cell lines that include blood, lung, colon, CNS, skin, ovarian, renal, prostate, and breast cancers, it was found that compound 5g was able to suppress 60 and 70% of tumor growth in leukemia SR and renal RXF 393 cell lines, respectively. Moreover, an ADME study indicated a suitable profile of compound 5g concerning cell permeability and blood-brain barrier (BBB) impermeability, avoiding possible CNS side effects. Accordingly, compound 5g is reported as a potential lead towards novel antiproliferative marine-derived kinase modulators.

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Leucettamine B analogs and their carborane derivative as potential anti-cancer agents: Design, synthesis, and biological evaluation

Cited by 13 publications

References 64 publications

Development of Marine-Derived Compounds for Cancer Therapy

Development of Marine-Derived Compounds for Cancer Therapy

Design, Synthesis, and Anticancer Activity of Cinnamoylated Barbituric Acid Derivatives

Development of New Meridianin/Leucettine-Derived Hybrid Small Molecules as Nanomolar Multi-Kinase Inhibitors with Antitumor Activity

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