Anticancer Potential of Coumarin derivatives: A Review

 

Raj K. Prasad*, Kavita R. Loksh

Department of Pharmacy, Oriental University, Indore, Madhya Pradesh – 453555.

 

ABSTRACT:

Cancer can conquer or feast on nearly all portions of the body. The cumulative illness and high humanity of cancer generate an innumerable claims for the expansion of innovative anticancer drugs. Coumarin (known as 1,2-benzopyrone or o-hydroxycinnamic acid-8-lactone) encompasses a huge class of phenolic offshoots that originate in plants and they are entailed of bonded benzene and a-pyrone rings. Numerous studies have exposed that several substituents on the coumarin essential structure stimulus different biological activities. Coumarin advert a character of pathways in cancer like kinase inhibition, cell cycle annexation, angiogenesis inhibition, telomerase inhibition, antimitotic activity, carbonic anhydrase inhibition, monocarboxylate transporters inhibition, aromatase inhibition, and sulfatase inhibition. Coumarin moiety is a beneficial template for the progress of novel anticancer agents.

 

 

INTRODUCTION:

Tumor disease, an assorted group of diseases categorized by the unrestrained growth of irregular cells, is a main worldwide problem. It is a lethal disease upright succeeding to cardiovascular disease with disease and humanity. Although the cancer investigation has directed to several innovative and active resolutions, the medications used as treatments have strong boundaries and inappropriately malignancy is expected as the main root of death in the upcoming time.^1,2 Presently there is enormous logical and commercial attention to the finding of effective, safe,and discriminatory anticancer drugs. Anti-cancer drugs are cytotoxic and revelation unembellished side effects mainly on regular multiplying tissues such as the hematopoietic system. Several cytotoxic agents are collective in anticancer treatment management, and offer better results with fewer side effects^3,4.

 

Presently, the mixture of chemotherapy, radiotherapy, and surgery suggestions the best consequences for cancer patients. Such combinations have been positively used in the behavior of specific cancer types, for example, Hodgkin’s lymphoma, testicular cancer, and various leukemias⁵.

 

The designation of coumarin chemical class has been resultant from Coumarouna odorata Aube (Dipteryx odorata), as the meekest member has been inaccessible for the first time. Coumarins chemically fit the benzopyrones family⁶. Coumarins (known as 1,2-benzopyrone or o-hydroxycinnamic acid-8-lactone) include a huge class of phenolic derivatives create in plants and they are containedbonded benzene and a-pyrone rings (Figure 1), first recognized in 1820 and revelation a vanilla-like or a newlymowedhay fragrance. Artificial making of coumarin ongoing since 1820 andhas been cast-off in the manufacture of flavorings and perfumes since 1868. Over the1300 coumarins have been recognized, chiefly as secondary metabolites ingreen plants in fungi and bacteria^7,8.

 

 

It is a naturallyoccurring compound being present in anextensive varietyof plantswith cassia, lavender, yellow sweetclover, and woodruff. Itis exceedingly present in some essential oils, particularly cinnamon bark oil and lavender oil.

 

Coumarin is also originated in fruits (e.g. bilberry, cloudberry), green tea, and additional foods like fixative, enhance the odor of essential oils in perfumes, toiletsoaps, toothpaste, and hair preparations, and in tobaccoproducts to enhance and fix the natural taste, flavorand aroma^9,10.

 

Coumarins spot a character of pathways in cancerlike kinase inhibition, cell cycle annexation, angiogenesis inhibition, telomerase inhibition, antimitotic activity, carbonic anhydrase inhibition, monocarboxylate transporters inhibition, aromatase inhibition, and sulfatase inhibition^11,12. Numerouspharmacological actions of coumarin centerwhich comprises antibacterial^13-18, cyclooxygenaseinhibition¹⁹, antimutagenic²⁰, hunting of reactive oxygen species (ROS)^21,22 anti-inflammatory^23-26, anticoagulant^27,28 lipoxygenases^29,30 CNS stimulants³¹, antithrombotic^32,33, vasodilatory^34,35, and anticancer activity^36-39.

 

Thus, the coumarin moiety is a beneficial template for the expansion of new anticancer agents. In several reviews, the various developments and the applications of coumarin derivatives as possible anticancer agents have already been summarized. This review will attentionto the currentexpansion of coumarin hybrids as optimistic anticancer agents.

 

 

 

 

Figure 1: Structure of bioactive natural coumarin and derivatives

 

Anticancer Activity:

Numerous coumarin derivatives derived from plants, fruits, and seeds (Figure 2) demonstrated potential in vitro and in vivo anticancer activity,^40–43 so naturally derived coumarin derivatives can assist as appreciated leads for additional design of supplementary active analogs. Some structure is reported in the following figure-

 

 

Structure	Biological Source
(Isolated from the roots of Peucedanumpraeruptorum Dunn)	Flavonoids including scopoletinwere isolated from Psephelluspyrrhoblepharus by Tastanet al.,
(Isolated from Saposhnikoviadivaricata (Turcz.).	(Isolated from seeds of Euphorbia lathyris L.,)
(It is sesquiterpene coumarin isolated from the root extract of Heptapteraanatolica)	(It isderived from Daphne oleoides)
Isolated from Vaccinium emarginatum	Psoralidin a natural furanocoumarin isolated from Psoralea corylifolia L.,
(A natural sesquiterpene coumarin, isolated from the roots of Ferulaferulaeoides)		(Galbanic acid, isolated from the resin of medicinal herbFerulaasafetida)

Figure 2. Coumarin derivatives derived from plants, fruits, and seeds

 

Coumarin Hybrids/Dimers:

Cancer is a very multifaceted disease and cannot be easily frozen with a solitary drug or with blends of drugs. Therefore, the treatment direction of a high dose of a single drug and blend of drugs that run to critical side effects and drug-drug interactions, which has havebe diminished. This molecular hybridization is based on the ingraining of two or more active compounds into one molecule without varying their innovative therapeutic worth⁴⁴. Hybrid molecules and dimers have the latent to upsurge the activity, overcome the drug resistance, and improve the specificity^45,46. Therefore, hybridization of coumarin fraction with additional anticancer pharmacophores or dimerization of coumarin may provide promising anticancer candidates.Molecular hybridization techniques can be intimate as-

 

a.    Linking technique (focuses on linking the two pharmacophores via a flexible linker or spacer)

b.    Fusing technique (done via covalently linking two bioactive pharmacophores; usually, a condensation reaction between the functional groups of each component)

c.    Merging technique (synthesized by a cyclization reaction with common parts in their structure finishedsmall in size as compared to hybrids containing linker and fused hybrid)

 

M. Holiyachi et.al.⁴⁷ have developed and produced coumarin-benzimidazole hybrid molecules Benzimidazole  nucleus is a fundamental heterocycle that can beused for an extensive spectrum of pharmacological actions. Some of the coumarin-3-benzimidazoles (Figure 2 A-C) have been generated using a hybridization strategy, which was partitioned for their anticancer activities on different cell lines. Amongthese structures, A and B (Figure 2) show more than 50% inhibitionagainst all the cell lines against leukemia cancer⁴⁸. Whereas, structureC (Figure 2) exhibits excellent antiviral as well as anti-HIVactivity⁴⁹. Calculated LC50 (Concentration of drug instigating 50% cell kill), TGI (Concentration of drug causing total inhibitionof cell growth), and GI50 (Concentration of drug instigating50% inhibition of cell growth) values at different concentrations (10, 20, 40 and 80mg/mL)^50,51.

 

Nasraet.al. synthesized⁵² and assessed coumarin derivativesusing anticancer activityin contradiction of resistant pancreatic cells and drugssubtle cell lines such as Hep-G2 and CCRF.Compounds 1-4 were created to be extra potent than the orientation drug doxorubicin.

 

Koneni V. Sashidharaet al.^{53, 54} reported the waytrailed for the research of coumarin derivativesand coumarin–chalcone hybrids is exemplifiedin Scheme, 5.Lamya H. et al.⁵⁵discussed the series of new coumarin derivatives resonant 1,2,4-triazole or 1,2,4-triazolo[3,4-b] thiadiazole moieties 6, were synthesized and assessedin vitro as anti-cancer in the humanoidcolon cancer cell line (HCT116). J. Dandriyal, et al.⁵⁶was also reported C-4 stand in for CoumarinDerivatives belong toanticancer agents7, C-4 replaced coumarin derivatives traildissimilar pathways to mark cancer likeselective estrogen receptor modulator, sulphatase embarrassment, aromatase inhibition, and downregulator,17βHSD3 inhibition, cell cycle arrest, Cdc25 inhibition, protein kinase inhibition,TNF-α inhibition, inhibition of HDAC, DNA intercalation, microtubulin inhibition, apoptosisinhibition.

 

Musa et al.⁵⁷also studiedin vitro anti-cancer activity of about 3-arylcoumarin derivatives in lung cancer cell lines (A549 cancer). The morebioactive compound was found, 8–(acetyloxy)-3-(4-methanesulfonyl phenyl)-2-oxo2Hchromen7-yl acetate, 8 a compound which displayeddiscerning cytotoxicity, producing cell seizure in the S phase of thecell cycle. Jamieret al. alsoproduced chalcone-coumarin derivatives and evaluated them for cytotoxic activity contrary todissimilar cancer cell lines, where the compound on 9 had the most cytotoxic activity found against ovarian cancer (OVCAR).

 

 

Mert O. Karata et al.⁵⁸was synthesized coumarin-benzimidazole hybrids (6-substituted-4-chloromethylene coumarin derivatives) in instruction to explore their cytotoxicactivities. Cytotoxic properties of all compoundswere tested against PC-3 and A2780 cancercelllinesand the structure of the best active compounds are given at 10-13. H.Y. Leeal. ⁵⁹designed and synthesized anew series, (Figure 5) of coumarin-based benzamides asHDAC inhibitors. Histone deacetylase wasthe striking therapeutic target for the action ofcancer and additional diseases. The cytotoxicityactivity of all the synthesized compoundswas assessed for six humanoid cancercell lines. In theinvestigation done by the researchers the fourcompounds (2a, 2b, 2c, 2d) (Figure 3) exhibitedcytotoxic with IC50. Among all of them, compound2a shows a higher potency for HDAC1 inhibitionwith an IC50 value.

 

 

S. No.	R1	R2	R3
2a	H	-OCH2CH3	H
2b	H	4-Br-Benzyloxy	H
2c	H	4-OCH3-Benzyloxy	H
2d	H	3, 4 Di- Benzyloxy	H

Figure 3. Coumarin based benzamides as HDAC inhibitors

 

K.V. Sashidhara, et al.⁶⁰, designed and synthesis a novelseries of coumarin and thiazole derivatives and evaluatedtheir α-glucosidase repressive activity. Among all of the tested molecules from 6a-e (Figure4), compound 6e was originated to be the maximum activeagent in the collection of coumarin thiazole derivatives.

 

S. No.	R	S. NO.	R1	R2	S. NO.
6a	4-OCH3	7b		5, 6-dimethyl	-CH3
6b	2-OH
6c	4-OH
6d	3, 4-tBu, 2-OH	7d		5-CH3	-CH3
6e	3, 5-Cl
Figure 4. coumarin thiazole derivatives.		Figure 5. 3, 7-disubstituted coumarin derivatives

 

Yubin Wang et al.⁶¹ was also intended, synthesized, and assessed 3, 7-disubstituted coumarin off shoots in vitro as cytotoxic compounds. Maximum of the agents displayed reasonable to potent anti-proliferative activity against K562 cells. Compounds 7b and 7d, (Figure 5) remained selected to evaluate the attention of 50% growth inhibition (GI50). Mazaahir Kidwaia et al.⁶² was studieda newsuccession of coumarin fused benzothiazepines was preparedvia a link of ortho aminothiophenol with in situ produced 3-benzylidenechroman-2,4-diones. These newagents werepartitionedfor their in vitro antioxidant activity against the free radical form of ABTS and anticancer activityagainst U87 human glioma cells. Inthe MTT assay, compound 14 showed the best activity at 9.8µg/ml followed by 15 at 19µg/ml.

 

S. Gurrapuet al.^63,64, studiednovel N, N-dialkyl carboxy coumarins werecreated as more potent cytotoxic agents via hang-up of monocarboxylate transporter 1 (MCT1) and assessed for their in vitro MCT1 inhibition activity, MTT cancer cell feasibility, bidirectional Caco-2 cell penetrability, and steadiness in human and liver microsomes. In vivo cancerdevelopment inhibition studies in mice demonstrate that thecontender compound 16 displays important solitary agent activity in MCT1 expressing GL261-luc2 syngraft model but does not demonstrate momentous activity in MCT4 expressing MDA-MB-231xenograft model, representing the discrimination of 16 for MCT1 stating tumors.

 

14	15
16	17
18	19

 

Hany A. El-Sheriefet al.⁶⁵ were examining a synthetic method constructed on molecularhybridization approach throughattachinga nitric oxide-releasing moiety, oxime, tocoumarin–chalcone hybrids. Also prepared in vitro antiproliferative activity of some compounds displayed reasonable activity (growing inhibition values = 45.85, 40.86, 39.25 for compound 17 against leukemia, CNS, and breast cytotoxic cells, respectively). Also, IC50=9.62 and 14.40 for compounds 18 and 19, correspondingly in contradiction of breast Michigan Cancer Foundation-7 cell lines.

 

Zhi Xu et al.⁶⁶ was reported the design and synthesis of a novelcustomary of tetraethylene glycol tethered isatin–coumarin hybrids 7d-l,20 as cytotoxic agents against in vitro antitumor activities against drug-sensitive HepG2, Hela, A549, DU145, SKOV3, HepG2, Hela, A549 and MCF-7 as well as drug-resistant MCF-7/DOX (doxorubicin-resistant MCF-7) human cancer cell lines (IC50: 11.90 to >50μM).Sobhi M. Gomhaet al.⁶⁷, a novel series of 2-(2-oxo-2Hchromene- 3-carbonyl)-5-phenyl-4-((2-phenylhydrazine) methyl)-2,4-dihydro-3H-pyrazol-3-ones were synthesized and also cyclized to 3-(3-phenyl-4,6-disubstituted-1,6-dihydropyrazolo[3,4-c]pyrazole-1-carbonyl)-2H-chromen-2-ones. They were studiedin vitro growth inhibitory activity of the synthesized compounds against hepatocellular carcinoma (HepG2) cell line was studied in assessment with doxorubicin as a standard drug with MTT assay and the results exposedauspicious activities of compounds, 21-23 with IC50 equal 0.92±0.22, 1.43±0.19, and 2.17± 0.21μM, correspondingly.

 

 

Gejjalagere S. Lingarajuet al.⁶⁸ A set of innovative coumarin-tiedisoxazolines were synthesized and evaluated for their cytotoxic strength against human melanoma cancer cell line (UACC 903) as well as fibroblast normal cell line (FF2441). Initial results exposed that some of these coumarins tethered isoxazolines, 24-27 showed important antiproliferative effects contrary to human melanoma cancer (UACC 903) with IC50 values of 8.8, 10.5, 9.2, and 4.5 Μmrespectively.

 

S. No.	R1	R2	S. No.	R1	R2
7d	H	NOH	7i	F	NOCH3
7e	CH3	NOH	7j	H	NOC2H5
7f	F	NOH	7k	CH3	NOC2H5
7g	H	NOCH3	7l	F	NOC2H5
7h	CH3	NOCH3

 

 

21	22		23
24		25
26		27

 

Nerella S. Goud et al.⁶⁹ A set of new morpholines connected coumarin-triazole hybrids have been synthesized and assessed for their anti-proliferative potential on a sheet of five human cancer cell lines specifically, bone (MG-63), lung (A549), breast (MDA-MB-231), colon (HCT-15) and liver (HepG2), using MTT assay. Amongst all, compound 28 exhibited important growing inhibition against MG-63 cells through an IC50 value of 0.80±0.22μ M. Eman A. Fayed et al.⁷⁰ designed and synthesized a new set of coumarin-pyridine/fused pyridine hybrids with anticancer activity, which was evaluated against human cancer cell lines MCF-7, HCT-116, HepG-2, and A549. Compounds 29-31 showed the most potent growth inhibitory activities with IC50 values ranging from 1.1 to 2.4μM, against the MCF-7 cell line.

 

Belma Z. Kurtet al.⁷¹ synthesized and screeneda series of new coumarin–chalconederivatives comprising urea moiety for their in vitro antiproliferativeactivities against the cancer cell lines (H4IIE and HepG2). Amongst the produced compounds, 32revealedimproved inhibitionof H4IIE linked to Sorafenib. Compound 33 also showed better inhibition against HepG2 than Sorafenib.

 

 

29

30

31

 

 

 

CONCLUSIONS:

Coumarins are an extensive class of usual and synthetic compounds that exhibited useful pharmacological effects. Coumarins unveiled antitumor activities at diverse phases of cancer development over numerous mechanisms. In this review, we have strained to bounce a wide-ranging summary of the extreme recent information in this area. In this article, we rereadexistingexpansions of coumarin hybrid and derivative anticancer agents in contradiction of various cell lines. In the current study, we have made an effort to categorizecoumarin-based anticancer agents rendering to the sort and position of the key pharmacophoric substituent on the coumarin fundamental structure. It is also supposed that this assessment is obliging for medicinal chemists to rational design and progress of additional active and less toxic anticancer drugs holding coumarin framework.

 

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Received on 09.08.2021       Modified on 17.12.2021

Accepted on 16.05.2022   ©Asian Pharma Press All Right Reserved