Quercetagetin and Patuletin: Antiproliferative, Necrotic and Apoptotic Activity in Tumor Cell Lines
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molecules Article Quercetagetin and Patuletin: Antiproliferative, Necrotic and Apoptotic Activity in Tumor Cell Lines Jesús J. Alvarado-Sansininea 1, Luis Sánchez-Sánchez 2, Hugo López-Muñoz 2, María L. Escobar 3 , Fernando Flores-Guzmán 2, Rosario Tavera-Hernández 1 and Manuel Jiménez-Estrada 1,* 1 Laboratorio 2-10, Departamento de Productos Naturales, Instituto de Química, Universidad Nacional Autónoma de México, 04510 Ciudad de México, Mexico; [email protected] (J.J.A.-S.); [email protected] (R.T.-H.) 2 Laboratorio 6, 2do piso, UMIEZ, Facultad de Estudios Superiores Zaragoza, Universidad Nacional Autónoma de México, 09230 Ciudad de México, Mexico; [email protected] (L.S.-S.); [email protected] (H.L.-M.); [email protected] (F.F.-G.) 3 Laboratorio de Microscopía Electrónica, Departamento de Biología Celular, Facultad de Ciencias, Universidad Nacional Autónoma de México, 04510 Ciudad de México, Mexico; [email protected] * Correspondence: [email protected]; Tel.: +52-(55)-56-22-44-30 Received: 22 August 2018; Accepted: 4 October 2018; Published: 9 October 2018 Abstract: Quercetagetin and patuletin were extracted by the same method from two different Tagetes species that have multiple uses in folk medicine in Mexico and around the globe, one of which is as an anticancer agent. Their biological activity (IC50 and necrotic, apoptotic and selective activities of these flavonols) was evaluated and compared to that of quercetin, examining specifically the effects of C6 substitution among quercetin, quercetagetin and patuletin. We find that the presence of a methoxyl group in C6 enhances their potency. Keywords: necrotic; apoptosis; quercetin; quercetagetin; patuletin 1. Introduction Cancer is one of the most severe public health problems worldwide. The urgent need to obtain new drugs to treat it arises from the fact that conventional treatments cause many side effects that negatively impact patients’ quality of life. This has fostered the use of plant extracts and their metabolites as sources of active compounds [1]. Plants are still widely-used for medicinal purposes by the indigenous peoples in Mexico, and the biological activity of many plant derivatives has been evaluated and shown to have medicinal importance [2]. The genus Tagetes belongs to the family Asteraceae. It is highly-esteemed as an ornamental plant, and in some parts of the world is has ritual-cultural importance [3]. Several species of Tagetes are found in Mexico, some known commonly as Cempasuchil or Cempoalxochitl [4]. Two representative species are Tagetes erecta and Tagetes patula [5], both of which have important therapeutic potential due to their antiparasitic, antimalarial, anti-inflammatory, antitumorogenic and antiviral effects [6]. Tagetes flowers contain different classes of natural products [7], including terpenes, carotenoids and flavonoids, which are known to have pharmacological effects [8]. Differences in their molecular structures may be responsible for their different pharmacological properties [9]. Specifically, the genus Tagetes has many kinds of flavonoids [10]. Of these, quercetagetin and patuletin present distinct inhibitory activity [11]. In the present study, we implemented a method to obtain quercetagetin and patuletin from Tagetes erecta and Tagetes patula, respectively [12,13], and performed a structure-activity Molecules 2018, 23, 2579; doi:10.3390/molecules23102579 www.mdpi.com/journal/molecules Molecules 2018, 23, 2579 2 of 18 Molecules 2017, 22, x FOR PEER REVIEW 2 of 18 relationship (SAR) study [14], focused on their anticancer properties by comparing them to Molecules 2017, 22, x FOR PEER REVIEW 2 of 18 quercetinFlavonoids [15]. are polyphenolic compounds with a C6-C3-C6 phenylbenzopyrone structure (Figure 1a) and they exhibit great structural diversity due to their various hydroxylation, methoxylation, FlavonoidsFlavonoids are are polyphenolic polyphenolic compounds compounds with with a C6 a-C C3-C6-C6 phenylbenzopyrone3-C6 phenylbenzopyrone structure structure (Figure (Figureglycosylation1a) and1a) they and exhibitand they acylation exhibit great great structural patterns structural [16]. diversity diversityThe basic du duee structureto totheir their various of various the flavonoid hydroxylation, hydroxylation, nucleus methoxylation,methoxylation, has different glycosylationsubstitutionglycosylation patterns andand acylationacylation in the A, patternspatterns B and [[16].C16 rings]. TheThe that basicbasic result structurestructure in various ofof thethe subgroups, flavonoidflavonoidnucleus nucleusone of which hashas differentdifferent are the substitutionflavonols,substitution which patterns possess in the thea 3-hydroxyflavone A, A, B B and and C C rings rings structure that that result result (Figure in invarious various1b). Examples subgroups, subgroups, of thisone one type of which of of which flavonoid are arethe theareflavonols, flavonols,the compounds which which possess quercetin, possess a 3-hydroxyflavone amyricetin 3-hydroxyflavone and structurekaempfer structure (Figureol [17]. (Figure 1b).Flavonoids Examples1b). Examplesdisplay of this diverse type of this of biologicalflavonoid type of flavonoidactivities,are the compounds areincluding the compounds quercetin, chemopreventive quercetin, myricetin myricetinandand kaempferchemot andherapeuticol kaempferol [17]. Flavonoids effects [17]. Flavonoidson display cancer. diverse displayThe followingbiological diverse biologicalmechanismsactivities, activities,including of action including chemopreventivehave been chemopreventive reported: and carcinogen chemot and chemotherapeutic herapeuticinactivation, effects antiproliferation, effects on oncancer. cancer. cell-cycleThe The followingfollowing arrest, mechanismsinductionmechanisms of ofapoptosis,of actionaction havehave inhibition beenbeen reported:reported: of angiogenic carcinogen processes, inactivation, modulation antiproliferation, of multi-drug cell-cycle resistance, arrest, and inductionantioxidativeinduction of apoptosis, apoptosis,activity [18,19]. inhibition inhibition of of angiogenic angiogenic pr processes,ocesses, modulation modulation of multi-drug of multi-drug resistance, resistance, and andantioxidative antioxidative activity activity [18,19]. [18, 19]. Figure 1. (a) Base structure of flavonoids; (b) Structure of flavonols. FigureFigure 1.1. ((aa)) BaseBase structurestructure ofof flavonoids;flavonoids; ((bb)) StructureStructure ofof flavonols.flavonols. Some structure-activity relationship studies have been conducted, and they indicate that the presenceSomeSome of structure-activitystructure-activity the C2=C3 double relationshiprelationship bond and studiesstudiesthe hydroxylation havehave beenbeen conducted,patternconducted, of flavonoids andand theythey indicateindicateinfluence thatthat tumor thethe presenceproliferationpresence ofof the themodulation C2=C3C2=C3 doubledouble [20]. bondbondIn this andand regard, thethe hydroxylationhydroxylation research has patternpatternshown ofofthat flavonoidsflavonoids hydroxylated influenceinfluence flavonoids tumortumor proliferationpossessproliferation stronger modulation modulation inhibitory [20 [20]. ].activity In thisIn this regard,on cancerregard, research cells research than has shown permethoxylatedhas shown that hydroxylated that hydroxylatedflavonoids, flavonoids and flavonoids that possess C3- strongerhydroxylationpossess inhibitorystronger is inhibitoryimportant activity on activityfor cancer this cells onactivity. cancer than permethoxylated Apigenin,cells than forpermethoxylated example, flavonoids, which and flavonoids, thatlacks C3-hydroxylation a 3-OHand that group, C3- ispresentshydroxylation important lower for antiproliferativeis thisimportant activity. for Apigenin, activitythis activity. than for kaempf example,Apigenin,erol which [21].for example,The lacks catechol a 3-OHwhich group group, lacks in ring presentsa 3-OH B enhances group, lower antiproliferativeanticancerpresents lower activity antiproliferative activity [22]. There than are kaempferol activity few studies than [21 kaempf ].of Thesubserol catecholtituents [21]. atThe group C6 catechol in in relation ring group B to enhances anticancer in ring B anticancer enhances activity, activitybutanticancer flavonols [22 ].activity There like are[22].quercetin, few There studies quareercetagetin offew substituents studies and of subs atpatuletin C6tituents in relation all at have C6 to in anticancer the relation aforementioned activity,to anticancer but structural flavonols activity, likecharacteristicsbut quercetin,flavonols quercetagetinlikethat quercetin,seem to andbe qu important patuletinercetagetin allfor and haveantiproliferative patuletin the aforementioned all activity.have the structural The aforementioned only characteristics difference structural among that seemthesecharacteristics tocompounds be important that is seem the for C6 antiproliferativeto group be important substituent, activity.for antiproliferativeas querce The onlytin has difference activity.a C6-H, amongquercetagetinThe only these difference compounds has a C6-OH, among is theandthese C6 patuletin compounds group substituent,has ais C6-OMethe C6 as group quercetin(Figure substituent, 2). has Given a C6-H, asthis querce quercetagetinbackground,tin has a theC6-H, has present a C6-OH,quercetagetin study and was patuletin has designed a C6-OH, has to a C6-OMecontributeand patuletin (Figure to the has2 ).study a Given C6-OMe of this the background,(Figurerole of 2).C6 Givensubstitution