Synthesis and cytotoxicity of novel 14α-<i>O</i>-(1,4-disubstituted-1,2,3-triazolyl) ester derivatives of andrographolide

Mokenapelli, Sudhakar; Gutam, Madhu; Vadiyaala, Naveen; Yerrabelli, Jayaprakash Rao; Banerjee, Somesh; Roy, Partha; Kancha, Rama Krishna; Kunduru, Bharathi Reddy; Sagurthi, Someswar Rao; Chitneni, Prasad Rao

doi:10.1080/14786419.2019.1628746

Cited by 11 publications

(6 citation statements)

References 15 publications

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“…These derivatives were obtained from the propargyl ester via Cu(I)-catalyzed click chemistry. Of the compounds synthesized and tested for cytotoxic activity in three cell lines, i.e., HCT-15 (colorectal cancer), HeLa (cervical cancer) and K562 (leukemia), the R = para-chlorophenyl-substituted triazole derivative proved more active in HCT-15 cells, whereas the R = para-bromobenzyl-substituted triazole compound was the most potent in K562 cells, while maintaining cell viability in the healthy MRC-5 cell line (Scheme 2) [42]. An additional modification of both C3 and C19 alcohol functions by esterification (3,19disuccinate and 3,19-dinicotinate) was also tested on the most active para-chlorobenzylidene derivative.…”

Section: Lactone Modification At Position C14mentioning

confidence: 99%

Synthetic Modifications of Andrographolide Targeting New Potential Anticancer Drug Candidates: A Comprehensive Overview

Messire,

Rollin,

Gillaizeau

et al. 2024

Molecules

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This review collects the synthetic modifications performed on andrographolide, a natural molecule derived from Andrographis paniculata, for oncology applications. Various pharmacomodulations were carried out, and the products were tested on different cancer cell lines. The impact of these modifications was analyzed with the aim of mapping the positions essential for activity to facilitate future research in this field. However, this study makes it clear that, in addition to structural modifications of the molecule, which can result in varying degrees of effectiveness in targeting interactions, the lipophilic capacity of the structures obtained through hemisynthesis is of significant importance.

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Section: Lactone Modification At Position C14mentioning

confidence: 99%

Synthetic Modifications of Andrographolide Targeting New Potential Anticancer Drug Candidates: A Comprehensive Overview

Messire,

Rollin,

Gillaizeau

et al. 2024

Molecules

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“…The aliphatic ester enhances the cytotoxic activity of Andro and the double bond between C-8 and C-17, in addition to the lactone and its conjugated double bond, maybe the central structure in which it acts [ 58 ]. In general, Andro and GA provide an alternative and complementary strategy for imatinib-resistant CML by inhibiting BCR-ABL function through a different mechanism than that of imatinib [ 59 , 60 , 61 ]. 8-hydroxydaidzein (8-OHD, 7,8,4′-trihydroxyisoflavone) is a hydroxylated derivative of daidzein isolated from fermented soybean products.…”

Section: Hematologic Tumorsmentioning

confidence: 99%

Research Progress of Natural Small-Molecule Compounds Related to Tumor Differentiation

Liu

Sun

2022

Molecules

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Tumor differentiation is a therapeutic strategy aimed at reactivating the endogenous differentiation program of cancer cells and inducing cancer cells to mature and differentiate into other types of cells. It has been found that a variety of natural small-molecule drugs can induce tumor cell differentiation both in vitro and in vivo. Relevant molecules involved in the differentiation process may be potential therapeutic targets for tumor cells. Compared with synthetic drugs, natural small-molecule antitumor compounds have the characteristics of wide sources, structural diversity and low toxicity. In addition, natural drugs with structural modification and transformation have relatively concentrated targets and enhanced efficacy. Therefore, using natural small-molecule compounds to induce malignant cell differentiation represents a more targeted and potential low-toxicity means of tumor treatment. In this review, we focus on natural small-molecule compounds that induce differentiation of myeloid leukemia cells, osteoblasts and other malignant cells into functional cells by regulating signaling pathways and the expression of specific genes. We provide a reference for the subsequent development of natural small molecules for antitumor applications and promote the development of differentiation therapy.

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“…4,32−35 Previous studies of the structure−activity relationships (SARs) of andrographolide have shown that esters on hydroxyl groups present at the C-3, C-19, and C-14 positions enhance pharmacological activities of andrographolide (1) relevant to its anticancer activity; e.g., 14-acetylandrographolide, 36 8,17epoxy-3,19,14 ester andrographolide, 37 14-cinnamoyl-8,17epoxy-andrographolide (DRF-3188), 37,38 andrographolide-14α-O-iodoacetate, 39 14-succinylandrographolide, 40 and 14α-O- (1,4-disubstituted-1,2,3-triazolyl) are biologically active synthetically modified ester derivatives of andrographolide (Figure 1). 41 Realizing the fact that introduction of an ester group at positions C-3 and C-19 enhances the cytotoxicity of the parent molecule (1) and that no attempt has so far been made to link ester at the C-17 position of andrographolide (1), we therefore have decided to introduce an ester at the C-17 position (site selective) without affecting the other functionalities of andrographolide such as the α-alkylidene-γ-butyrolactone moiety and C-3, C-19 hydroxyl functional group. In this research work, we report site-selective synthesis of C-17 ester derivatives of andrographolide, and further, all synthesized compounds were in vitro tested for their ability to inhibit the growth of four human cancer cell lines: A594 (lung carcinoma), PC3 (prostate carcinoma), MCF-7 (breast carcinoma), and HCT-116 (colon carcinoma).…”

Section: Introductionmentioning

confidence: 99%

“…, 14-acetylandrographolide, 36 8,17-epoxy-3,19,14 ester andrographolide, 37 14-cinnamoyl-8,17-epoxy-andrographolide (DRF-3188), 37 , 38 andrographolide-14α- O -iodoacetate, 39 14-succinylandrographolide, 40 and 14α- O -(1,4-disubstituted-1,2,3-triazolyl) are biologically active synthetically modified ester derivatives of andrographolide ( Figure 1 ). 41 …”

Section: Introductionmentioning

confidence: 99%

Site-Selective Synthesis of C-17 Ester Derivatives of Natural Andrographolide for Evaluation as a Potential Anticancer Agent

et al. 2023

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A library of 57 compounds of natural andrographolide was designed, synthesized, and screened for in vitro studies against four human cancer cell lines: A594, PC-3, MCF-7, and HCT-116. Most of the synthesized compounds displayed better cytotoxic profile against all tested cells compared to the parent andrographolide (1). The tested semisynthetic derivatives of andrographolide were found to be more sensitive toward lung carcinoma (A594) and prostate carcinoma (PC-3) cell lines. Among the synthesized compounds, the C-17 p-methoxy phenyl ester analog 8s inhibited cell proliferation effectively in A549 (IC50: 6.6 μM) and PC-3 (IC50: 5.9 μM) cell variants, and compound 9s exhibited the most potent activity against the A594 cell line, with an IC50 value of 3.5 μM. Further anticancer mechanistic investigation demonstrated that compound 9s displayed nuclear morphological changes and increased reactive oxygen species (ROS) with disturbed mitochondrial membrane potential (MMP) that can lead to apoptosis. To know the exact structure confirmation of intermediate compounds 4 and 5, single X-ray crystallography was performed, which supported the complete reaction design of this work.

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Synthesis and cytotoxicity of novel 14α-O-(1,4-disubstituted-1,2,3-triazolyl) ester derivatives of andrographolide

Cited by 11 publications

References 15 publications

Synthetic Modifications of Andrographolide Targeting New Potential Anticancer Drug Candidates: A Comprehensive Overview

Synthetic Modifications of Andrographolide Targeting New Potential Anticancer Drug Candidates: A Comprehensive Overview

Research Progress of Natural Small-Molecule Compounds Related to Tumor Differentiation

Site-Selective Synthesis of C-17 Ester Derivatives of Natural Andrographolide for Evaluation as a Potential Anticancer Agent

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