Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents

Dhuguru, Jyothi; Skouta, Rachid

doi:10.3390/molecules25071615

Cited by 93 publications

(74 citation statements)

References 107 publications

(187 reference statements)

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“…Of the numerous halogenases, the flavin-dependent halogenases (FDHs) have been a focus for biotechnologists, due to their high substrate-and regio-specificity, and their ability to function independently of carrier proteins that bind the substrate. A subgroup of FDHs targeting the indole moiety of tryptophan are the most well studied group of FDHs, due to the prevalence of indole as a building block in both biology and synthetic chemistry (Frese and Sewald, 2015;Dhuguru and Skouta, 2020). Mechanistically, these tryptophan halogenases are similar to haem-dependent haloperoxidases and vanadiumdependent haloperoxidases in that they form a hypohalous acid (HOX) intermediate.…”

Section: Halogenation In Nature and Pharmacologymentioning

confidence: 99%

“…They therefore allowed the halogenases to target tryptophan and expressed an E. coli-derived tryptophanase (TnaA) to convert this into a halogenated indole, which could then be converted, with varying efficiencies, to chloro-indican in planta. As indole is a common biosynthetic precursor, and a privileged heterocyclic scaffold (Dhuguru and Skouta, 2020), this system may help to unlock derivative space surrounding a number of diverse metabolites.…”

Section: Kong Et Al 2020mentioning

confidence: 99%

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Deploying Microbial Synthesis for Halogenating and Diversifying Medicinal Alkaloid Scaffolds

Bradley

Zhang

Jensen

2020

Front. Bioeng. Biotechnol.

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Plants produce some of the most potent therapeutics and have been used for thousands of years to treat human diseases. Today, many medicinal natural products are still extracted from source plants at scale as their complexity precludes total synthesis from bulk chemicals. However, extraction from plants can be an unreliable and lowyielding source for human therapeutics, making the supply chain for some of these life-saving medicines expensive and unstable. There has therefore been significant interest in refactoring these plant pathways in genetically tractable microbes, which grow more reliably and where the plant pathways can be more easily engineered to improve the titer, rate and yield of medicinal natural products. In addition, refactoring plant biosynthetic pathways in microbes also offers the possibility to explore new-tonature chemistry more systematically, and thereby help expand the chemical space that can be probed for drugs as well as enable the study of pharmacological properties of such new-to-nature chemistry. This perspective will review the recent progress toward heterologous production of plant medicinal alkaloids in microbial systems. In particular, we focus on the refactoring of halogenated alkaloids in yeast, which has created an unprecedented opportunity for biosynthesis of previously inaccessible new-to-nature variants of the natural alkaloid scaffolds.

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Section: Halogenation In Nature and Pharmacologymentioning

confidence: 99%

Section: Kong Et Al 2020mentioning

confidence: 99%

Deploying Microbial Synthesis for Halogenating and Diversifying Medicinal Alkaloid Scaffolds

Bradley

Zhang

Jensen

2020

Front. Bioeng. Biotechnol.

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“…In the metaphysical healing concept, Spirtualism concepts like prayers, invocations, or incantations have been offered to some mysterious and powerful forces in the various belief concept system like exorcism, divination, libation etc., were also been practicing to heal several diseases, how ever, scientific validation and documentation is still challenging [5,6]. Some of plants used in herbalism by traditional african healers are Foeniculum vulgare Mill [7], Rauvolfia serpentina Linn [8], Cinchona pubescens Vahl [9], Digitalis purpurea Linn [10], etc.…”

Section: Introductionmentioning

confidence: 99%

Traditional African Medicine

Chaitanya¹,

Baye²,

Ali³

et al. 2022

Natural Medicinal Plants

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African traditional medicine is defined as one of the holistic health care system comprised of three levels of specializations namely divination, spiritualism, and herbalism. The traditional healer provides healing services based on culture, religious background, knowledge, attitudes, and beliefs that are prevalent in his community. Hence the current chapter focuses on the different types of african healing system, traditional healers, traditional practices and modern herbalism and also describes the phytochemical and pharmacological evidences of the traditional african herbs like Acanthus montanus (Acanthaceae), Amaranthus spinosus (Amaranthaceae), Bridelia ferruginea (Euphorbiaceae) etc.

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“…Moreover, two marketed RTK inhibitors, sunitinib and osimertinib, possess an indole core. Sunitinib, a PDGFR and VEGFR inhibitor, was approved in the treatment of renal cell carcinoma and gastrointestinal stromal tumor, whereas osimertinib, an EGFR inhibitor, was approved in the treatment of NSCLC [38][39][40]. On the other hand, it was also demonstrated that indomethacin, an indole-based COX-1 and COX-2 inhibitor, exhibited anti-lung cancer and anti-CRC activity through chemical modifications on the main structure [41][42][43][44][45].…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Silico Evaluation of Anticancer Activity of New Indole-Based 1,3,4-Oxadiazoles as EGFR and COX-2 Inhibitors

et al. 2020

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Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are crucial targetable enzymes in cancer management. Therefore, herein, new 2-[(5-((1H-indol-3-yl)methyl)-1,3,4-oxadiazol-2-yl)thio]-N-(thiazol/benzothiazol-2-yl)acetamides (2a–i) were designed and synthesized as EGFR and COX-2 inhibitors. The cytotoxic effects of compounds 2a–i on HCT116 human colorectal carcinoma, A549 human lung adenocarcinoma, and A375 human melanoma cell lines were determined using MTT assay. 2-[(5-((1H-Indol-3-yl)methyl)-1,3,4-oxadiazol-2-yl)thio]-N-(6-ethoxybenzothiazol-2-yl)acetamide (2e) exhibited the most significant anticancer activity against HCT116, A549, and A375 cell lines with IC50 values of 6.43 ± 0.72 μM, 9.62 ± 1.14 μM, and 8.07 ± 1.36 μM, respectively, when compared with erlotinib (IC50 = 17.86 ± 3.22 μM, 19.41 ± 2.38 μM, and 23.81 ± 4.17 μM, respectively). Further mechanistic assays demonstrated that compound 2e enhanced apoptosis (28.35%) in HCT116 cells more significantly than erlotinib (7.42%) and caused notable EGFR inhibition with an IC50 value of 2.80 ± 0.52 μM when compared with erlotinib (IC50 = 0.04 ± 0.01 μM). However, compound 2e did not cause any significant COX-2 inhibition, indicating that this compound showed COX-independent anticancer activity. The molecular docking study of compound 2e emphasized that the benzothiazole ring of this compound occupied the allosteric pocket in the EGFR active site. In conclusion, compound 2e is a promising EGFR inhibitor that warrants further clinical investigations.

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Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents

Cited by 93 publications

References 107 publications

Deploying Microbial Synthesis for Halogenating and Diversifying Medicinal Alkaloid Scaffolds

Deploying Microbial Synthesis for Halogenating and Diversifying Medicinal Alkaloid Scaffolds

Traditional African Medicine

In Vitro and In Silico Evaluation of Anticancer Activity of New Indole-Based 1,3,4-Oxadiazoles as EGFR and COX-2 Inhibitors

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