Synthesis and biological evaluation of amino analogs of Ludartin: Potent and selective cytotoxic agents

Lone, Shabir H.; Bhat, Khursheed Ahmad; Shakeel-u-Rehman,; Majeed, Rabiya; Hamid, Abid; Khuroo, Mohammad Akbar

doi:10.1016/j.bmcl.2013.06.068

Cited by 25 publications

(12 citation statements)

References 20 publications

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“…A rigorous literature precedent revealed that there are no such reports underscoring the structure activity relationship (SAR) linking the effect of aryl substituents tethered via amide linkage to the parent molecule on the antioxidant activity of the resulting synthetic analogs. Keeping these facts in mind as well as our previous work on natural product based synthesis, we directed this work towards the synthesis of a diverse series of novel amide derivatives of biological interest using RA as the key template. All its synthesized analogs were then subjected to DPPH, hydroxyl radical and reducing power assay to check their antioxidant potential.…”

Section: Introductionmentioning

confidence: 99%

New Semi-Synthetic Rosmarinic Acid-Based Amide Derivatives as Effective Antioxidants

Ayoob

Lone²,

Masood-ur-Rahman

et al. 2017

ChemistrySelect

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Rosmarinic acid (RA), a bioactive compound isolated from Rosmarinus officinalis exhibits multiple pharmacological activities, including antioxidant, anti‐allergic and anti‐inflammatory effects. Herein, we report the synthesis of new series of amide analogs of rosmarinic acid along with their antioxidant potential. Highest DPPH scavenging effect was observed in case of (E)‐3‐(3,4‐dihydroxy‐phenyl)‐1‐((4‐fluorophenyl)amino)‐1‐oxopropan‐2‐yl‐3‐(3,4dihydroxy phenyl)acrylate (RA‐15) displaying an IC50 of 3.19 μg/ml compared to standard ascorbic acid (IC50=4.09 μg/ml). However (E)‐3‐(3,4‐dihydroxyphenyl)‐1‐((4‐hydroxyphenyl)amino)‐1‐oxopropan‐2‐yl‐3‐(3, 4‐dihydroxyphenyl)acrylate (RA‐10) displayed the highest hydroxy radical scavenging effect exhibiting an IC50 of 8.98 μg/ml compared to standard ascorbic acid (IC50=9.00 μg/ml). This study thus, provides an important aspect with regard to the use of these rosmarinic acid‐based antioxidants in food industry as dietary supplements.

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Section: Introductionmentioning

confidence: 99%

New Semi-Synthetic Rosmarinic Acid-Based Amide Derivatives as Effective Antioxidants

Ayoob

Lone²,

Masood-ur-Rahman

et al. 2017

ChemistrySelect

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“…[16] All of these methodologies led to new structures that were usually established by X-ray crystal analyses. [18] Bhat et al also www.eurjoc.org obtained amino analogues of ludartin (31), a potent and selective cytotoxic agent, [19] by use of a Michael addition at the exocyclic double bond of the α-methylene γ-lactone as a key step (Scheme 3). Furthermore, in 1989 Barbetti and co-workers synthesized a sequence of 13-phenylseleno derivatives of guaianolides from grossheimin (27) and cynaropicrin (28); these compounds showed cytotoxic activity against κB cell cultures.…”

Section: Guaianolide Strategiesmentioning

confidence: 99%

Trends in the Synthesis and Functionalization of Guaianolides

2015

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Guaianolides constitute a large and diverse group of biologically active sesquiterpenes. Guaianolide and seco‐guaianolides can also be used as, for example, scaffolds for the development of new active molecules that are readily accessible by synthetic methods. Nevertheless, these lactones often have complex structures that make their synthesis difficult. The aim of this microreview is to provide an overview of the developments in guaianolide synthesis by the two major synthetic strategies: semi‐synthesis and total synthesis. Partial and total syntheses of guaianolides are described, with particular emphasis placed on the methods reported in the last decade. The methods discussed include rearrangements, cycloadditions, ring‐closing metathesis, the use of transition‐metal catalysts, photochemical reactions, and other recently developed techniques as key steps.

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“…Aromatase, or estrogen synthase, has always been considered the most promising target for the endocrine treatment of breast cancer [3]. Among all inhibitors, nonsteroidal inhibitors have proved to be the best therapeutic agents, as they reversibly inhibit the enzyme [2,4]. Aromatase inhibitors (AIs) are further divided into categories based on the order in which they were discovered or synthesized: first-, second-, and third-generation AIs.…”

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confidence: 99%

“…However, the introduction of one more ethyl group, instead of methyl furnishing a diethylamino ludartin (20), enhanced the selectivity of the parent ludartin against the MCF-7 cell line with an IC 50 of 1.21 µM. This analog was previously [4] found to be active only against THP-1 (3.5 µM) and HCT-116 (3.7 µM). However, epoxidation of this analog led to a loss of bioactivity.…”

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confidence: 99%

Diastereoselective Synthesis of 1,10β-Epoxy-11R,13-dihydroamino Analogs of Ludartin as Anti-breast Cancer Agents

Lone

Bhat

Malik

et al. 2016

PMIO

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Abstract! Diverse 11R,13-dihydroamino and 1,10β-epoxy-11R,13-dihydroamino analogs of ludartin were synthesized using a highly diastereoselective Michael addition and epoxidation reaction. The semisynthetic analogs were characterized using rigorous spectral data analysis. All the compounds were subjected to sulphorhodamine B cytotoxicity screening against a panel of three breast cancer cells, viz., T47D, MCF-7, and MDA-MB 231. Among the synthesized analogs, compounds 11, 19, and 20 proved to be active against the breast cancer cell lines. Compound 11 represents an epoxy analog of arglabin (5), which is a noteworthy and clinically significant antitumor agent and exhibited an IC 50 s of 0.75 µM and 1.20 µM against MCF-7 and MDA MB-231 cell lines, respectively. Compounds 19 and 20 displayed selectivity among the three breast cancer cell lines and were active against MCF-7 cell lines only displaying IC 50 s of 1.00 and 1.21 µM, respectively. This study provides initial structure-activity relationship data on ludartin and its analogs against breast cancer cell lines based on the previous literature reports of ludartin as an aromatase inhibitor.Key words ludartin · amino analogs · epoxy amino analogs · breast cancer · cytotoxicity Supporting information available online at http://www.thieme-connect.de/products Leaving apart the cancers of skin, breast cancer is the most frequently occurring cancer in women [1]. It ranks second as a cause of tumor-related death only after lung cancer. Presently, it is envisaged that one in eight American women will develop breast cancer sometime during her life. Two-thirds of breast cancer tumors are hormone dependent, requiring estrogen to flourish [2]. An effective approach to treat such hormone-dependent cancer involves interfering with hormone production. Aromatase, or estrogen synthase, has always been considered the most promising target for the endocrine treatment of breast cancer [3]. Among all inhibitors, nonsteroidal inhibitors have proved to be the best therapeutic agents, as they reversibly inhibit the enzyme [2,4]. Aromatase inhibitors (AIs) are further divided into categories based on the order in which they were discovered or synthesized: first-, second-, and third-generation AIs. Currently, the third generation aromatase inhibitors are triazole-derived AIs and are approved as front-line therapy for early and advanced cases of breast cancer in postmenopausal women [1,5,6]. Brueggemeier and Cruz [1] framed a list of 65 molecules with potent aromatase inhibitory activity, among which the four sesquiterpene lactones, designated 1, 2, 3, and 4 (l " Fig. 1), display strong aromatase inhibition. The research group opined that the triazole-based compounds display a potent inhibitory effect. Taking a cue from this literature, we previously synthesized the 1, 2, 3 triazole-based analogs [7] of this molecule to develop more potent and less toxic compounds, and screened them against breast cancer cells. Among all of the synthesized compounds, only one compound, namely, (11R)-13-[1-(...

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Synthesis and biological evaluation of amino analogs of Ludartin: Potent and selective cytotoxic agents

Cited by 25 publications

References 20 publications

New Semi-Synthetic Rosmarinic Acid-Based Amide Derivatives as Effective Antioxidants

New Semi-Synthetic Rosmarinic Acid-Based Amide Derivatives as Effective Antioxidants

Trends in the Synthesis and Functionalization of Guaianolides

Diastereoselective Synthesis of 1,10β-Epoxy-11R,13-dihydroamino Analogs of Ludartin as Anti-breast Cancer Agents

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