Biologically active coumarins as inhibitors of HIV-1
TL;DR: The objective of this review is to evaluate data on coumarins’ potent activity with respect to the inhibition of HIV-reverse transcriptase, HIV-integrase or HIV-protease.
Abstract: Considerable progress has been made in recent years in the field of drug development against HIV. Many different kinds of natural products, including coumarins, have been found to be active in anti-HIV models and are thus undergoing further investigation. This review demonstrates the variety of coumarins with unique mechanisms of action in the different stages of HIV replication. The discovery and development of coumarins as anti-HIV agents has expanded in the past two decades. Most of the studies have been focused on the inhibitory activity of reverse transcriptase, but anti-integrase and antiprotease activities were also described. The objective of this review is to evaluate data on coumarins’ potent activity with respect to the inhibition of HIV-reverse transcriptase, HIV-integrase or HIV-protease. Recent requirements for potential anti-HIV agents increasingly require adequate definition of the mechanism of action as well as definition of toxic effects and this also applies to natural as well as synthe...
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TL;DR: This review considers and incorporates the most recently published literature on coumarins as related to their antioxidant properties, and updates and expands the 2006 review by the same author.
Abstract: Coumarins, a well-known class of naturally occurring compounds, display a remarkable array of biochemical and pharmacological actions, some of which suggest that certain members of this group of compounds may significantly affect the function of various mammalian cellular systems. The development of coumarins as antioxidant agents has attracted much attention in recent years. Coumarins afford an opportunity for the discovery of new antioxidants with truly novel mechanisms of action. This review updates and expands the 2006 review by the same author. The review considers and incorporates the most recently published literature on coumarins as related to their antioxidant properties. A lot of coumarins have been identified from natural sources, especially green plants. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. Beyond doubt, a deep understanding of the mechanisms of existing synthetic and natural coumarins will build the basis for the rational design.
303 citations
30 Sep 2015
TL;DR: There may be as many as 4,000 different phytochemicals having potential activity against several diseases such as cancer and metabolic or degenerative diseases, but not all are established as essential nutrients.
Abstract: Phytochemicals are chemical compounds that occur naturally in the plant kingdom. Some are responsible for the organoleptic properties of the natural sources in which they are present. The term is generally used to refer to those chemicals that may have biological significance, for example carotenoids, flavonoids, coumarins, or chromones, but not all are established as essential nutrients. There may be as many as 4,000 different phytochemicals having potential activity against several diseases such as cancer and metabolic or degenerative diseases.
128 citations
Cites background from "Biologically active coumarins as in..."
...The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution [68]....
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...Several recent reviews summarize and highlight advances in the application of coumarins, especially concerning their antioxidant and anti‐ cancer properties [62-70]....
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TL;DR: The improved SAR will provide further insight into the rational improvement of coumarin hybrids with astounding strength against multidrug-resistant bacteria.
82 citations
TL;DR: This review delves further into the study of natural and synthetic coumarins as COX-inhibitors, which is still in its nascent stage and believes there is scope for a lot of development.
73 citations
TL;DR: Two new bioinspired coumarin probes were synthesized and fully characterized and behaved as supramolecular chemosensors, which have been selective for the heavy element Hg(2+), with a concomitant change of color from pink to dark red/brown and an increase of size up to 100-fold.
Abstract: Emissive molecular probes based on amino acid moieties are very appealing because of their application as new building blocks in peptide synthesis. Two new bioinspired coumarin probes (L1 and L2) w...
32 citations
References
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TL;DR: Calanolide A was active not only against the AZT-resistant G-9106 strain of HIV-1 but also against the pyridinone-resistant A17 strain, which was of particular interest since the A17 virus is highly resistant to previously known HIV- 1 specific, non-nucleoside RT inhibitors.
Abstract: Eight new coumarin compounds (1-8) were isolated by anti-HIV bioassay-guided fractionation of an extract of Calophyllum lanigerum. The structures of calanolide A (1), 12-acetoxycalanolide A (2), 12-methoxycalanolide A (3), calanolide B (4), 12-methoxycalanolide B (5), calanolide C (6) and related derivatives 7 and 8 were solved by extensive spectroscopic analyses, particularly HMQC, HMBC, and difference NOE NMR experiments. The absolute stereochemistry of calanolide A (1) and calanolide B (4) was established by a modified Mosher's method. Calanolides A (1) and B (4) were completely protective against HIV-1 replication and cytopathicity (EC50 values of 0.1 microM and 0.4 microM, respectively), but were inactive against HIV-2. Some of the related compounds also showed evidence of anti-HIV-1 activity. Studies with purified bacterial recombinant reverse transcriptases (RT) revealed that the calanolides are HIV-1 specific RT inhibitors. Moreover, calanolide A was active not only against the AZT-resistant G-9106 strain of HIV-1 but also against the pyridinone-resistant A17 strain. This was of particular interest since the A17 virus is highly resistant to previously known HIV-1 specific, non-nucleoside RT inhibitors (e.g., TIBO; BI-RG-587; L693,593) which comprise a structurally diverse but apparently common pharmacologic class. The calanolides represent a substantial departure from the known class and therefore provide a novel new anti-HIV chemotype for drug development.
540 citations
"Biologically active coumarins as in..." refers background in this paper
...(+)-calanolide A (Figure 1A), (+)-[10R,11S,12S]10,11-trans-dihydro-12-hydroxy-6,6,10,11tetramethyl-4-propyl-2H,6H-benzo[1,2-b:3,4b ́:5,6-b ́ ́]tripyran-2-one, first isolated from a tropical tree (Calophyllum lanigerum) in Malaysia, is a novel NNRTI with potent activity against HIV-1 [6–8]....
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TL;DR: There is still a long way to go until the authors know which cytotoxic agent will clinically be suitable for what tumor entity for treatment, because promising data have been reported for a series of these agents, and the results from different coumarins with various tumor lines are contradictory in part.
Abstract: Coumarins, an old class of compounds, are naturally occurring benzopyrene derivatives. A lot of coumarins have been identified from natural sources, especially green plants. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. Coumarins have attracted intense interest in recent years because of their diverse pharmacological properties. Among these properties, their cytotoxic effects were most extensively examined. In this review, their broad range of effects on the tumors as shown by various in vitro and in vivo experiments and clinical studies are discussed. Hence, these cytotoxic coumarins represent an exploitable source of new anticancer agents, which might also help addressing side-toxicity and resistance phenomena. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. In this review, plant derived coumarins and their synthetic analogues were systematically evaluated based on their plant origin, structure-activity relationship and anticancer efficacy. Owing the their diverse effects and inconclusive results from different in vitro studies, the mechanism of their action is not yet fully understood and correlation of effects with chemical structures is not conclusive at the moment. It is the objective of this review to summarize experimental data for different coumarins, used as cytotoxic agents, because promising data have been reported for a series of these agents. Yet, the results from different coumarins with various tumor lines are contradictory in part. We therefore conclude that there is still a long way to go until we know which cytotoxic agent will clinically be suitable for what tumor entity for treatment. Their ability to bind metal ions represents an additional means of modulating their pharmacological responses.
455 citations
"Biologically active coumarins as in..." refers background in this paper
...A variety of coumarin natural products exhibit interesting pharmacological and potentially useful therapeutic properties [2,3]....
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TL;DR: A dicamphanoyl‐khellactone analog, which was discovered and developed in the laboratory, and calanolide A are currently in preclinical studies and clinical trials, respectively.
Abstract: Numerous plant-derived compounds have been evaluated for inhibitory effects against HIV replication, and some coumarins have been found to inhibit different stages in the HIV replication cycle. This review article describes recent progress in the discovery, structure modification, and structure-activity relationship studies of potent anti-HIV coumarin derivatives. A dicamphanoyl-khellactone (DCK) analog, which was discovered and developed in our laboratory, and calanolide A are currently in preclinical studies and clinical trials, respectively.
438 citations
"Biologically active coumarins as in..." refers background in this paper
...(2007) 1(3) future science group Synthetic 3’,4’-di-O-(-)-camphanoyl-(+)-ciskhellactone analogues Numerous plant-derived compounds have been evaluated for inhibitory effects against HIV replication, and among them, the coumarins calanolide A and 3 ́,4 ́-di-O-(S)-camphanoyl(+)-cis-khellactone (DCK) analog have been found to represent potent anti-HIV coumarin derivatives [21]....
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...Coriandrin ‡‡ RT [21]...
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TL;DR: In this paper, a series of 3,5-bis(arylidene)-4-piperidones, as chalcone analogues carrying variety of aryl and heteroaryl groups, were synthesized and screened for their in vitro antiviral and antitumor activities at the National Cancer Institute (NCI).
Abstract: A new series of 3,5-bis(arylidene)-4-piperidones, as chalcone analogues carrying variety of aryl and heteroaryl groups, pyrazolo[4,3-c]pyridines, pyrido[4,3-d]pyrimidines, and pyrido[3,2-c]pyridines, carrying an arylidene moiety, and a series of pyrano[3,2-c]pyridines, as flavone and coumarin isosteres, were synthesized and screened for their in vitro antiviral and antitumor activities at the National Cancer Institute (NCI). Compounds 9 and 18 proved to be active against herpes simplex virus-1 (HSV-1), while compound 13 showed moderate activity against human immunodeficiency virus-1 (HIV-1). Compounds 14, 26, 28, 33, and 35 exhibited a broad spectrum antitumor activity. In addition, compounds 26, 33, and 35 proved to be of moderate selectivity toward leukemia cell lines. The pyrano[3,2-c]pyridines heterocyclic system proved to be the most active antitumors among the investigated heterocycles.
349 citations
"Biologically active coumarins as in..." refers background in this paper
...A new series of 3,5-bis(arylidene)-4-piperidones, as chalcone analogues carrying a variety of aryl and heteroaryl groups, pyrazolo[4,3-c]pyridines, pyridolo[4,3c]pyrimidines, and pyrido[4,3-c]-pyridines, carrying an arylidene moiety, and a series of pyrano[3,2c]pyridines, as flavone and coumarin isosteres, were synthesized [31] and screened for their in vitro antiviral and antitumor activities at the National Cancer Institute....
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TL;DR: The inhibition of HIV-1 integrase by flavones and related compounds was investigated biochemically and by means of structure-activity relationships and the potential for building upon a general pharmacophore to generate target specificity was discussed.
328 citations
"Biologically active coumarins as in..." refers background in this paper
...The major classes of IN inhibitors that have been reported to date include DNA-binding agents, topoisomerase inhibitors, aurintricarboxylic acid and cosalene analogues, caffeic acid phenylethyl ester, and bis-catechols or other hydroxylated aromatic compounds [33–40]....
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