Abietane Diterpenoids As Potential Drugs

5 CATALYZER THE FIFTH ISSUE OF CATALYZER MAGAZINE 19/07/2020

ABIETANE DITERPENOIDS AS POTENTIAL DRUGS

Abietanes are naturally word “turpentine”. Each isoprene occurring diterpenoids that unit also called a “C5 building haveAbietane been isolated Diterpenoids from several as Potentialblock” or Drugs hemi-terpene; they terrestrial plant families are linked to form terpenes in includingGülaçtı Topçu Lamiaceae (Labiatae), “head-to-tail” fashion, in general. Asteraceae, Celastraceae, Therefore, monoterpenes are and Boraginaceae, and resins formed from 2 isoprene units (10 Abietanes are naturally occurring diterpenoids that have been isolated from several terrestrial Sildi: which from conifers belonging to the C’s), sesquiterpenes from 3 units familiesplant families Cupressaceae, including Lamiaceae Pinaceae, (Labiatae), (15Asteraceae, C’s), diterpenes Celastraceae, fromand Boraginaceae 4 units , Podocarpaceae,and resins from conifers Phyllocladaceae, belonging to the families(20 Cupressaceae,C’s), and sesterterpenes Pinaceae, Podocarpaceae, from andPhylloclad Araucariaceae.aceae, and Araucariaceae. 5 units (25 C’s), while triterpenes Sildi: e are from 6 units (30 C’s) and Secondary metabolites metabolites of plants of can be classifiedtetraterpenes, namely as fromterpenoids 8 units and (40 steroids, Sildi: ; plantsflavonoids can and be other classified, phenolics, namely and alkaloids, C’s). which all play an important role in their asdefense terpenoids mechanisms, and such steroids, as fighting with herbivores, pests, and pathogens as well as other Sildi: to

flavonoidstypes of external and damage other. Asphenolics, one of the secondaryMono- metabolites and sesquiterpenoids of plants, terpenoids are Sildi: s and alkaloids, which all play an are the main constituents composed of isoprene (2-methyl-1,3-butadiene) units. The name "terpene" is derived from the Sildi: formed important role in their defense of the essential oils of all mechanisms,word “turpentine”. such Each isopreneas fighting unit also calledplants a “C5 building and flowers block” or and hemi they-terpene ; they Sildi: , withare linked herbivores, to form terpenes pests, in and“head -to-tail” fashion,give in them general. their Therefore, special monoterpenes smell are pathogensformed from 2 as isoprene well asunits other (10 C’s), types sesquiterpenes and taste. Diterpenoids from 3 units (15 C’s), diterpenes are from of4 units external (20 C’s), damage. and sesterterpenes As one offrom 5 unitscomposed (25 C’s), wh ofile fourtriterpenes isoprene are from units 6 units the(30 C’s) secondary and tetraterpenes metabolites from 8 unit ofs (40 C’s). with a core molecular formula Sildi: e

plants, terpenoids are composed C20H32to form different skeletons, ofMono isoprene- and sesquiterpenoids (2-methyl-1,3- are the main constituentssuch as of abietane, the essential kaurane, oils of all plants and butadieneflowers and )they units. give The them name their special smell andatisane, taste. Diterpenoids labdane, jatrophane,are composed of four Sildi: which occur “terpene” is derived from the tigliane, lathyrane, or taxane. isoprene units with a core molecular formula C20H32 to form different skeletons, such as abietane, kaurane, atisane, labdane, jatrophane, tigliane, lathyrane, or taxane. Sildi: h Sildi: , etc

Abietane skeleton Abietic acid Dehydroabietic acid Ferruginol

Abietane diterpenoids have three 6-membered cyclic rings (trans-fused A-B, and trans-fused

B-C rings) with an isopropyl side chain attached to C-13 on ring C. A simple example of them Sildi: is abietic acid (7,13-abietadien-18-oic acid), and dehydroabietic acid, which has an aromatic Sildi: The Sildi: for INTERNATIONAL CHEMISTRY OLYMPIAD MAGAZINE / ISTANBUL - TURKEY 2020

Taxodione Salvinolone 6-Hydroxysalvinolone

Abietane diterpenoids have three six-membered cyclic rings (trans- Some Salvia species afforded abietane diterpenoids that have opened Taxodione Salvinolone 6-Hydroxysalvinolone fused A-B, and trans-fused B-C rings) with an isopropyl side chain ring A, which are called seco-abietanes, such as aethiopinone and Some Salvia species afforded abietane diterpenoids that have opened ring A, which are called Sildi: which attached to C-13 on ring C. A simple example of them is abietic acid salvipisone [2,8]. (7,13-abietadien-18-oic acid), and dehydroabietic acid, which has seco-abietanes, such as aethiopinone and salvipisone [2,8]. Some Salvia species afforded abietane diterpenoids that have opened ring A, which are called Sildi: which an aromatic ring C, previously obtained during chemical studies starting from abietic acid. Another simple abietane diterpene withseco the -abietanes, such as aethiopinone and salvipisone [2,8]. aromatic ring C is ferruginol, first isolated in 1939 from the resin of thering miro C, previouslytree (Podocarpus obtained ferrugineus during chemical) endemic studies to starting New Zealandfrom abietic [1]. acid. Another simple abietane diterpene with the aromatic ring C is ferruginol, first isolated in 1939 from the resin Aromatic abietanes comprise the largest group of naturally occurring abietanesof the miro [1] t reeand (Podocarpus are the main ferr secondaryugineus) endemic metabolites to New ofZealand the Salvia [1]. Sildi: M Sildi: h L. (sage) plants belonging to the family Lamiaceae. The genus Salvia Aethiopinone Salvipisone Aromatic abietanes comprise the largest group of naturally occurring abietanes [1] and are the Sildi: species is represented by over 900 species throughout the world, and the bestmain known secondary Salvia metabolites species are of the S. miltiorrhizaSalvia L. (sage) (Danshen plants belonging or Tanshen) to the in family Lamiaceae. Sildi:Aethiopinone the Salvipisone China and other Asian countries, S. officinalis L. in Europe (sage), and Sildi: The genus Salvia is represented by over 900 species throughout the worldThe, and most theThe best interesting most known interesting re-arranged re-arranged abietanes abietanes were obtained were obtained from endemic from Anatolian Salvia Sildi: M S. fruticosa Mill. (syn: S. triloba L.) in Mediterranean countries, and S. Sildi: d endemic Anatolian Salvia species, such as S. microstegia Boiss. et M divinorumSalvia species L., a hallucinogenicare S. miltiorrhiza species, (Dansh enwhose or Tanshen) origin indates China back and tootherspecies Thethe Asian m,ost such cou interesting ntriesas S., S.microstegia re-arrangedSildi: (BrandtBoiss. abietanes ve etNeubauer Bal were. 1939)grow obtaineding in fromthe Binboğa endemic Mountains Anatolian Salvia(Turkey) , Sildi: Sildi: n Bal. growing in the Binboğa Mountains (Turkey), which afforded a Mazatecofficinalis hallucinogenic L. in Europe sage. (sage), Most and SalviaS. fruticosa species Mill. are (syn: rich S. in trilobaabietanespecies L.) in , Mediterraneansuch as S. microstegia Sildi: Boiss. family et Bal. growing in the Binboğa Mountains (Turkey), Sildi: n which affordedrearranged a rearranged tricyclic abietanetricyclic diterpene. abietane diterpene. Its structure Its structurewas elucidated was elucidated by a diterpenoids, while S. divinorum is rich in neo-clerodane diterpenoids. Sildi: most countries, and S. divinorum L., a hallucinogenic species, whose originwhich dates affordedby back a series toa rearrangedthe of NMR techniques,tricyclic 1 abietane such 13as diterpene. 1H and 13 ItsC NMR, structure COSY was elucidated by a In Turkey, Salvia species are represented by over 100 species (114series of NMR techniques, Sildi: such h as H and C NMR, COSY and 1D-NOE and SINEPT taxa),Mazatec and hallucinogenichalf of them are sage endemic. Most Salvia to Anatolia species (Asian are rich part in abietane of Turkey). seriesditerpenoids ofand NMR ,1D-NOE while techniques, S. and SINEPT such a experimentss 1H and 13C as NMR, well COSYas HRMS and analysis. 1D-NOE and SINEPT experimentsExamination as well as of HRMS its unusualSildi: analysis. Mediterra carbonnian Examination skeleton ofsuggested its unusual that carbon this skeleton suggested divinorum is rich in neo-clerodane diterpenoids. In Turkey, Salvia speciesexperiments are represented as well by as HRMSSildi: analysis. hallusinogenic Examination of its unusual carbon skeleton suggested During our group studies on Salvia species by Prof. Ulubelen and that this compound might be derived biogenetically fromfrom regularregular abietane abietane diterpene having a Sildi: its byover Prof. 100 Topcu, species over (114 140 taxa) abietane, and half diterpenoids of them are endemic were isolated to Anatolia (Asianthat this part diterpenecompound of Turkey ).havingmight be a threederived six-membered biogenetically Cfrom skeleton regular by abietane ring A diterpene having a three–six-membered C skeletonSildi: of the by ring A cleavage between C-4 and C-5, followed by Sildi: [2,7], at least half of them being new, and most ofring them C, previouslyhave an obtainedcleavage during chemical between studies C-4 and starting C-5, followed from abietic by recyclization acid. Another of sim C-4ple three–six-membered C skeletonSildi: being by ring A cleavage between C-4 and C-5, followed by Sildi: Sildi: aromaticDuring ourring group C. Their studies structures on Salvia were species elucidated by Prof. basedUlubelen on and 1D- by and recyclizationProf. Topcu,to C-11. overof C Therefore, -1440 to C-11. the Th finalerefore, product, the final named product microstegiol,, named microstegiol with a , with a seven- abietane diterpene with the aromatic ring C is ferruginol, first isolated in 1939 from the resin Sildi: 2D-NMRabietane and diterpenoids mass spectroscopic were isolated analyses [2,7], at least as well half asof UVthem and being IR new,recyclization and seven-memberedmost ofof Cthem-4 to C-11. ring Therefore, A, is optically the final active, product suggesting, named microstegiol that the , with a seven- Sildi: membered ring A, is optically active, suggesting that the rearrangement is under enzymatic Sildi: spectrophotometric measurements. of the miro tree (Podocarpusmemberedrearrangement ringferr uAgineus, is optically) endemicis under active toenzymatic New, suggest Zealand ingcontrol, that [1] .the and rearrang it was efoundment isto underbe enzymaticSildi: M Sildi: ed have an aromatic ring C. Their structures were elucidated based on 1D- and 2D-NMR and Sildi: ed control, andactive it wasagainst found P-388 to be lymphocytic active against leukemia P-388 lymphocyticcells (ED50 = 3.0leukemia mg/mL) cells (EDSildi:50 h = 3.0 Somemass abietane-type spectroscopic analyses diterpenoids as well have as UV a andpara IR-quinone spectrophotometricAromatic C ring, abietanes such measurements.control, comprise [3].and the Totalit was largest synthesis found group to beof of microstegiolactive naturally against occurring wasP-388 carried lymphocyticabietanes out by[1] leukemia Tajand and are Green thecells (ED 50 = 3.0 µg/mL) [3]. Total synthesis of microstegiol was carried out by Taj and Green and publishedSildi: species in Sildi: , R.A. as royleanone and horminone, or an ortho-quinone C ring, such µg/mL) [3]and. Total published synthesis in 2010 of microstegiol [9]. was carried out by Taj and Green and published in Sildi: , R.A. main secondary metabolites of the Salvia L. (sage) plants belonging to the family Lamiaceae. Sildi: the Sildi: J.R. asSome miltirone abietane [8], -buttype the diterpenoid last of theses have was a apara norditerpene-quinone C with ring ,19 such C2010 as [9]royleanone. and Sildi: J.R. 2010 [9]. Sildi: atoms.horminone, or an ortho-quinone C ring, such as miltironeThe genus [8] Salvia, but theis representedlast of these by was over a 900 speciesSildi: , throughout the world, and the best known Sildi: d Sildi: latter norditerpene with 19 C atoms. Salvia species are S. miltiorrhiza (Danshen or Tanshen) in China and other Asian countries, S. Sildi: (Brandt ve Neubauer 1939) Sildi: a officinalis L. in Europe (sage), and S. fruticosa Mill. (syn: S. triloba L.) in Mediterranean Sildi: family

countries, and S. divinorum L., a hallucinogenic species, whose origin dates back to the Sildi: most Sildi: h Mazatec hallucinogenic sage. Most Salvia species are rich in abietane diterpenoids, while S. Mediterranian Sildi: divinorum is rich in neo-clerodane diterpenoids. In Turkey, Salvia species are represented by Sildi: hallusinogenic MicrostegiolMicrostegiol SalvibretolSalvibretol CandidissiolCandidissiol Sildi: its over 100 species (114 taxa), and half of them are endemic to Anatolia (Asian part of Turkey). Sildi: of the Royleanone Horminone 6,7-DehydroroyleanoneDuring our group studiesMiltirone on Salvia species by Prof. Ulubelen and by Prof. Topcu, over 140 Sildi: being abietane diterpenoids wereAnother isolated endemic [2,7], at Salvialeast half species, of them S. candidissima being new, and, also most afforded of them a Furthermore, some abietanes contain an enone group in ring B conjugated to the re-arrangedaromatic ring abietaneSildi: with of an eight-membered ring A, which is very Furthermore, some abietanes contain an enone grouphave an in aromaticring B ring C. unusualTheir structure for naturals were compounds, elucidated andbased its on structure 1D- and was 2D identified-NMR and by conjugatedC such as taxodione,to the aromatic salvinolone ring, Cand such 6-hydroxysalvinolone as taxodione, salvinolone,. and Sildi: conjugated mass spectroscopic analysesextensive as well asNMR UV techniques and IR spectrophotometric running 1D and measurements.2D NMR experiments and 6-hydroxysalvinolone . named candidissiol [4]. Some abietane-type diterpenoids have a para-quinone C ring, such as royleanone and

horminone, or an ortho-quinone C ring, such as miltirone [8], but the last of these was a Sildi: , norditerpene with 19 C atoms. Sildi: latter Sildi: a

Taxodione TaxodioneSalvinolone Taxodione Salvinolone 6-HydroxysalvinoloneRoyleanone Salvinolone6- Hydroxysalvinolone Horminone6-Hydroxysalvinolone 6,7-Dehydroroyleanone Miltirone

Furthermore, some abietanes contain an enone group in ring B conjugated to the aromatic ring Sildi: of Some Salvia speciesSome afforded Salvia species abietaneSome afforded Salviaditerpenoids speciesabietane that afforded diterpenoids have open abietaneed that ring diterpenoids have A, whichopened arethat ring called have A, which opened areSildi: ring called which A, which areSildi: called which Sildi: which C such as taxodione, salvinolone, and 6-hydroxysalvinolone. Sildi: conjugated seco-abietanes, suchseco -asabietanes, aethiopinone suchseco as-andabietanes, aethiopinone salvipisone such [2,8]andas aethiopinone salvipisone. [2,8]and .salvipisone [2,8].

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Aethiopinone AethiopinoneSalvipisone Aethiopinone Salvipisone Salvipisone

The most interestingThe m reost-arranged interestingThe abietanes mreost-arranged interesting were abietanes obtained re-arranged fromwere endemic obtainedabietanes Anatolian fromwere endemic obtained Salvia Anatolian from endemicSildi: Salvia M Anatolian Sildi: Salvia M Sildi: M species, such asspecies S. microstegia, such as speciesBoiss.S. microstegia et, such Bal . asgrow Boiss. S. ingmicrostegia etin Bal the. growBinboğa Boiss.ing etinMountains Balthe. Binboğagrow (ingTurkey) Mountainsin the, Binboğa (Sildi:Turkey) nMountains, (Sildi:Turkey) n , Sildi: n which afforded whicha rearranged afforded tricyclic awhich rearranged abietaneafforded tricyclic diterpene.a rearranged abietane Its tricyclic structure diterpene. abietane was Its elucidated structure diterpene. was by Its a elucidated structure by was a elucidated by a series of NMR series techniques, of NMR such series techniques, as 1 Hof andNMR such13C techniques, aNMR,s 1H and COSY such13C and NMR, as 1 1DH - COSYandNOE 13 C and and NMR, SINEPT 1D -NOE COSY and and SINEPT 1D-NOE and SINEPT experiments as wellexperiments as HRMS as analysis.wellexperiments as HRMS Examination as analysis. well asof HRMSExaminationits unusual analysis. carbon of itsExamination skeletonunusual carbonsuggested of its skeleton unusual suggestedcarbon skeleton suggested that this compoundthat mightthis compound be derivedthat might this biogenetically compound be derived mightfrom biogenetically regular be derived abietane from biogenetically regular diterpene abietane havingfrom regularditerpene a abietane having diterpene a having a three–six-memberedthree –Csix skeleton-memberedthree by –C ringsix skeleton- membered A cleavage by ringC betweenskeleton A cleavage C by-4 ring and between CA- 5, cleavage followed C-4 and between by C- 5, followed C-4Sildi: and by C -5, followedSildi: by Sildi: recyclization of recyclizationC-4 to C-11. ofTh Crecyclizationerefore,-4 to C the-11. final Thof erefore,C product-4 to C the,- 11.named final Therefore, productmicrostegiol the, named final, with microstegiolproduct a seven, named- , with microstegiol Sildi:a seven - , withSildi: a seven - Sildi: Sildi: Sildi: Sildi: membered ring memberedA, is optically ring activeAmembered, is ,optically suggest ringing active A ,that is, opticallysuggestthe rearranging active thatement, thesuggest isrearrang undering thateenzymaticment the is rearrang under enzymaticement is under enzymatic Sildi: ed Sildi: ed Sildi: ed control, and it wascontrol, found and to itbe was activecontrol, found against and to beit P was-active388 found lymphocytic against to be P -active388 leukemia lymphocytic against cells P- 388 (EDleukemia lymphocytic50 = 3.0 cells (ED leukemia50 = 3.0 cells (ED50 = 3.0 µg/mL) [3]. Totalµg/mL) synthesis [3]. ofTotal microstegiolµ g/mL)synthesis [3] was.of Total microstegiol carried synthesis out bywas of Taj microstegiol carried and Green out by was and Taj carried published and Green out inby and Taj published andSildi: Green , R.A. in and publishedSildi: , R.A. in Sildi: , R.A. J.R. J.R. J.R. 2010 [9]. 2010 [9]. 2010 [9]. Sildi: Sildi: Sildi:

Microstegiol MicrostegiolSalvibretol Microstegiol SalvibretolCandidissiol Salvibretol Candidissiol Candidissiol

Another endemic Salvia species, S. candidissima, also afforded a re-arranged abietane with an Sildi: From a eight-membered ring A, which is very unusual for natural compounds, and its structure was identified by extensive NMR techniques running 1D and 2D NMR experiments and named Sildi: the candidissiol [4]. Sildi: as Sildi:

Salvibretol and its natural derivatives 1-oxosalvibretol and Multicaulins were isolated as a series of fully aromatic abietane 3-oxosalvibretol were isolated first from S. montbretii [5], and later diterpenoids;Salvia their microstegia skeleton Boiss.has 19 C atoms Salviasince montbretii they were Salvia multicaulis from a few other Salvia species [2,5], and their structure analyses converted into norabietanes from abietanes andBenth they. showed very Vahl. Salvibretol and its natural derivatives 1-oxosalvibretol and 3-oxosalvibretol were isolated first were elucidated by sophisticated NMR and mass techniques. The strong antituberculous activity against Mycobacterium tuberculosis formationfrom S. montbretii of salvibretol [5], and [5] laterfrom from microstegiol a few other through Salvia species Wagner– [2,5], and their [2,10]. structure Sildi: first Multicaulins were isolated as a series of fully aromatic abietane diterpenoids; their skeleton Sildi: , Meerweinanalyses wererearrangement elucidated by is sophistseen below,icated NMRwhich and is a mass very techniques common. The formation of Biçimlendirdi: Üst simge/Alt simgeAl, kesik çiziliDeğil carbocation reaction in natural products. has 19 C atomsSildi: since they were converted into norabietanes from abietanes and they showed Sildi: which salvibretol [5] from microstegiol through Wagner–Meerwein rearrangement is seen below, , very strongSildi: antituberculous activity against Mycobacterium tuberculosis [2,10]. Sildi: highly which is a very common carbocation reaction in natural products. Sildi: an Sildi: on Sildi: , Sildi: t Sildi: -

R= CH3: Multicaulin R= CH3: Multiorthoquinone R= H: Demethylmulticaulin R= H: Demethyl-multiorthoquinone

It is notable that the extracts of Salvia roots were found to be rich in diterpenoids, particularly Sildi: ice abietane diterpenoids, while their triterpenoids were isolated from the aerial parts rather than other parts.

Salvia microstegia Boiss et bal.

Salvia montbretii Benth. Salvia multicaulis Vahl

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Salvia triloba L. f. Salvia triloba L. with 3 lobe leaf Salvia officinalis L.

It is notable that the extracts of Salvia roots were found to be rich References in diterpenoids, particularly abietane diterpenoids, while their Salviatriterpenoids fruticosa Mill were. isolatedS. triloba from with the aerial3 lobe partsleaf rather thanSalvia other officinalis L. parts. [1] Brandt C. W.; Neubauer L. G. Miro resin. Part I. Ferruginol. J. Chem. S. fruticosaS. fruticosa Mill., also Mill named., also namedS. triloba S. trilobadue to due its leavesto its leaves with 3with lobe 3s, lobes, is a MediterraneanSoc. 1939 , 1031-1037.Sildi: n Mediterranean sage, although Greek people call it Greek sage, sage, although Greek people call it Greek sage, Lebanon people Lebanese sage, and Turkish Sildi: named Dalmatian people Dalmatian Sage Lebanon people Lebanese sage, [2] Topcu G.; Yucer, R.; Senol H. Bioactive constituents of Anatolian Sildi: call people Turkishand Turkish sage. Itspeople phytochemical Turkish sage. structure Its phytochemical [2] is fairly similar structure to th [2]at of EuropeanSalvia sage species., In: Salvia Biotechnology Georgiev, V.; Pavlov, A.; Eds; Springer InternationalSildi: as Publishing AG, part of Springer Nature, Cham, S. officinalisis fairly; the similarmain difference to that of is European observed sage,in their S. officinalisessential oil.; the S. main triloba contains almost difference is observed in their essential oil. S. triloba contains almost 2018, pp. 31-132,Sildi: 9783319739007. the no thujoneno, whilethujone, S. officinalis while S. officinalis is rich in isthujone rich in. Due thujone. to the Due presence to the ofpresence thujone, the European Sildi: ; [3] Ulubelen, A.; Topcu, G.; Tan, N.; Jin, L. J.; Cordell, G. A. Microstegiol, of thujone, the European Medicines Agency (EMA) allows max. 5 mg/ Sildi: , Medicines Agency (EMA) allows max. 5 mg/day thujone in medicinal plant products,a such rearranged as diterpene from Salvia microstegia. Phytochemistry 1992, day thujone in medicinal plant products, such as S. officinalisessential Sildi: for S. officinalis essential oil. Therefore, S. triloba is much more preferable and valuable 31in ,terms 2419-2421. oil. Therefore, S. triloba is much more preferable and valuable in Sildi: Because terms of its essential oil. Both species contain strong antioxidant of its essential oil. Both species contain strong antioxidant abietane diterpenoids, [4]and Ulubelen, the A.;Sildi: Topcu, carries G.; Tan, N. Diterpenoids from Salvia abietane diterpenoids, and the strongest ones are carnosol and candidissima. TetrahedronSildi: EMA ( Lett. 1992, 33, 7241-7244. strongest carnosic ones are acid. carnosol Carnosol and protets carnosic us acid. against Carnosol narrowing protects of the against cerebral narrowing of the Sildi: thujone amount as cerebral arteriesarteries carrying carrying blood blood to to the the brain. brain. Carnosic Carnosic acid acid increases increases the the body’s production[5] Topcu, of G.; Ulubelen, A. Abietane and rearranged abietane body’s production of glutathione, which is one of the most important diterpenes fromSildi: Salvia s montbretii. J. Nat. Prod. 1996, 59, 734-737. glutathioneantioxidants,, which is one helping of the to most protect important the brain antioxidants from free, help radicaling todamage. protect the brain from Sildi: bear free radical damage. [6] Topcu, G.; Eris,Sildi: C.; most Ulubelen, A. Rearranged abietane diterpenes from Salvia limbata. Phytochemistry 1996, 41, 1143-1147. Sildi: the Sildi: which [7] Ulubelen, A.; Sonmez, U.; Topcu, G. Diterpenoids from the roots of Salvia sclarea. PhytochemistrySildi: s 1997, 44, 1297-1299. Sildi: against [8] Hernández-Pérez, M.; Rabanal, R. M.; Arias, A. M. C.; de La Torre M. C.; Rodríguez, B. Aethiopinone, an antibacterial and cytotoxic agent from Salvia aethiopis roots. Pharm. Biology 2008, 37, 17-21.

Carnosol Carnosic acid [9] Taj, R. A.; Green, J. R. Nicholas reactions in the construction of cyclohepta[de]naphthalenes and cyclohepta[de]naphthalenones. The total synthesis of microstegiol. J. Org. Chem. 2010, 75, 8258-8270. Therefore, aromatic abietanes are a strong antioxidant, and some of them might be used in neuroprotectiveTherefore, and aromaticcardioprotective abietanes agents, are strongsuch as antioxidant, carnosol and and carnosic some acid. Some[10] of Secinti, the H.; Burmaoglu, S.; Altundas, R.; Secen, H. Total syntheses of them might be used in neuroprotective and cardioprotective of multicaulins via oxidative photocyclization of stilbenes. J. Nat. Prod. abietanesagents, that have such conjugated as carnosol aromatic and carnosic structures, acid. particularlyAbietanes having such asring taxodione C 2014 and , 677- , 2134-2137.Sildi: which hydroxysalvinoloneconjugated, withexhibited enone very or enol strong moiety cytotoxic on ring activity B, particularly against a such series as of cancer cell Sildi: on taxodione and 6-hydroxysalvinolone, exhibited very strong cytotoxic lines [2]. Thus, the potential impact of abietanes in the discovery of therapeutic drugs should Sildi: the activity against a series of cancer cell lines [2]. Thus, the potential Gülaçtı Topçu be considered.impact of abietanes in the discovery of therapeutic drugs should be considered. References Sildi: . [1] Brandt C. W.; Neubauer L. G. Miro resin. Part I. Ferruginol. J. Chem. Soc. 1939, 1031- Sildi: , 1037. Sildi: , [2] TopcuPAGE G.; Yucer,- 4 R.; Senol H. Bioactive constituents of Anatolian Salvia species. In: Sildi: a Salvia Biotechnology Georgiev, V.; Pavlov, A.; Eds; Springer International Publishing AG, Sildi: part of Springer Nature, Cham, 2018, pp. 31-132, 9783319739007. Sildi: [3] Ulubelen, A.; Topcu, G.; Tan, N.; Jin, L. J.; Cordell, G. A. Microstegiol, a rearranged Sildi: , diterpene from Salvia microstegia. Phytochemistry 1992, 31, 2419-2421. Sildi: MALATYA APRICOT

Flowering period of apricot

Apricot on the branch.

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Historical Perspective in Malatya where 53 thousand Agriculture and Production Dried apricot. people lived. Çelebi also wrote Apricot (Prunus armeniaca L.) that Malatya had apricots that In 2017, 536 thousand hectares is a plant whose homeland is were “red, yellow, white, juicy, of land worldwide was used for Central Asia and Western China. and succulent” and that when apricot production and 23.3% It is cultivated in regions with someone brought them home of this was in Turkey. Global a temperate climate zone from from the garden, they had fresh apricot production was 4.3 the Mediterranean to Australia. no choice but to run to keep million tons in 2017. Most of the According to historical sources, them fresh. More importantly, fresh apricot production in the it can be produced in many he stated that unimaginable world was in Turkey, with 985 countries including Turkistan, amounts of dried sheets of pulp thousand tons. According to 2018 Central Asia, and Western were made from the heaps of data, Turkey exports annually 71 China. Apricots were known and apricots, loaded onto wagons, thousand tons of apricots and cultivated in this region 5000 and transported to other ranks third in exports worldwide. years ago. It was brought to countries [2]. A total of 120 thousand tons Anatolia in the 1st century during of dried apricot exports were the expeditions of Alexander the Apricot Varieties Grown in reported worldwide, with 94 Great. It has become the second Malatya thousand tons (78.2%) from homeland of the apricot, as the Turkey. An important part of the climate and soil are suitable for Approximately 90-95% of the produced apricot is considered its cultivation [1]. apricot orchards in the region dried apricot. Turkey is a leader have been established with in dried apricot production, History of the Apricot in Malatya dried apricot varieties. While followed by Spain with 4.2% 73% of the cultivated apricot and Kirghizstan with 3.4%. With The first written records on varieties are Hacıhaliloğlu, 17% the many advantages of its apricot in Malatya are from are Kabaaşı, and the rest are special ecological conditions, 1655. The famous traveler Soğancı, Hasanbey, Çataloğlu, Malatya Province ranks first 1 Evliya Çelebi , who came to and zerdali (less than 1%) trees in production. Although the Malatya, mentioned about 7800 [2]. production of dried varieties is at orchards and 7 apricot varieties

1 For further information about the most famous Ottoman traveler of the 17th century, see: https://en.wikipedia.org/wiki/Evliya_%C3%87elebi

PAGE - 6 the forefront in this country, most small quantities [15]. Similarly, kayısı (Prunus armeniaca L.) Anthocyanins in Fruits, Vegetables of the apricots produced in the the vitamins found in apricot çeşitlerinin farklı ekolojilerdeki and Grains. Boca Raton, FL, USA: world are for daily consumption include provitamin A, C, K, E, fenolojik özelliklerinin CRC Press, 1993, p. 362. [3,4]. thiamine (B1), riboflavin (B2), belirlenmesi. Nevşehir Bilim ve niacin (B3), pyridoxine (B6), Teknoloji Dergisi 2016, 5, 179- [13] Ali, S.; Masud, T.; Abbasi K. S. Apricot Production folic acid (B9), and pantothenic 188. Physico-chemical characteristics acid [16]. In general, apricot is of apricot (Prunus armeniaca Approximately 770 thousand especially rich in vitamins A and [5] Tarımsal Ekonomi ve Politika L.) grown in northern areas of tons of apricot including zerdali C [17]. Apricot contains organic Geliştirme Enstitüsü. 2020 Ocak Pakistan. Scientia Horticulture species were produced last year acids, namely malic acid (500- Tarım Ürünleri Raporu: Kayısı 2011, 130, 386-392. in Turkey. Malatya has a special 900 mg/100 g] and citric acid Tarım Ürünleri Piyasa Raporu, position in Turkey with 401 (30-50 mg/100 g) as the main Ocak 2020. [14] Lichou, J.; Jay, M.; Vaysse, thousand tons of apricot, which acids; it has also been reported P.; Lespinasse, N. Reconnaitre is 52.1% of the total production to contain tartaric, succinic, [6] Asma B. M.; Gültek A.; Kan les Variétés d’Abricots. Editions [5]. Apricot fruit has become oxalic, galacturonic, kinic, T.; Birhanlı O. Kayısıda Kükürt CTIFL, France, 2003, p. 17-29. indispensable for Malatya due malonic, acetic, and fumaric Sorunu. 1. Baskı. Öz Gayret Ofset, [15] Hacıseferoğulları, H.; Gezer, to its production amount and its acid [18]. These acids, which are Malatya, Türkiye, 2005. İ.; Özcan, M. M.; MuratAsma, contribution to the economy [6]. natural components of many [7] Catoni, C.; Peters, A.; B. Post-harvest chemical and fruits and vegetables, reduce Medicine Schaefer, H. M. Life history physical–mechanical properties bacterial spoilage and provide trade-offs are influenced of some apricot varieties flavor, taste, and shelf stability. Various mechanisms in the by the diversity, availability cultivated in Turkey. J. Food Eng. They also play an important human body keep the oxidant and interactions of dietary 2007, 79, 364-373. role in maintaining quality and antioxidant defense antioxidants. Anim. Behav. 2008, and determining nutritional mechanisms in balance. Some of 76, 1107-1119. [16] Lee, S. K.; Kader, A. A. Pre- these are healthy nutrition and value. Apricot kernels contain a harvest and post-harvest factors dietary antioxidants. considerable amount of protein [8] Diplock, A. T.; Charleux, J. L.; influencing vitamin C content of and fat in 20-30% and 40-52%, Crozier-Willi, G.; Kok, F. J.; Rice- horticultural crops. Postharvest respectively [19]. The average Evans, C.; Roberfroid, M.; Stahl, Biol. Technol. 2000, 20, 207-220. The most prominent protein and fat ranges in apricot W.; Vina-Ribes, J. Functional food representatives of dietary fruit are 1.4-2.0% and 0.4-0.6%, science and defence against [17] Hasib, A.; Jaouad, A.; antioxidants are carotenoids, respectively. Despite the low reactive oxidative species. Brit. J. Mahrouz, M.; Khouili, M. HPLC ascorbate, tocopherols, and amounts, apricot fruit also Nutr. 1998, 80, 77-112. determination of organic acids flavonoids [8]. According to contains many essential amino in Moroccan apricots. Cienc. the recent literature, apricot acids [14]. [9] Parlakpinar, H.; Olmez, E.; Technol. Aliment. 2002, 3, 207- has significant antioxidant Acet, A.; Ozturk, F.; Tasdemir, 211. potential due to its content such Table 1: Proximate composition S.; Ates, B.; Gul, M.; Otlu, A. as vitamins A and C and some of apricot fruit [15]. Beneficial effects of apricot- [18] Bassi, D.; Bartolozzi, polyphenols like beta carotene F.; Muzzi, E. Patterns and [9]. heritability of carboxylic acids Ingredients Concentration (g/100 g fresh weight) and soluble sugars in fruits of Nutritional Potential Water 83.00 apricot (Prunus armeniaca L.). Plant Breeding 1996, 115, 67-70. Apricot is a fruit rich in Carbohydrates 11.00-13.00 carbohydrates, fiber, minerals, Protein 1.40 [19] Alpaslan, M.; Hayta, M. and vitamins among the hard Apricot kernel: physical and Fat 0.40 fruits (Table 1) (10). It contains chemical properties. Letters to many bioactive phytochemicals, Crude fiber 1.50-2.40 the editor. J. Am. Oil Chem. Soc. that is, polyphenols and Ash 0.74 2006, 83, 469- 471. carotenoids that have certain Hakan Parlakpınar roles in the biological system and are effective in preventing feeding on myocardial ischemia- oxidative stress damage [11]. References reperfusion injury in rats. Food These compounds also give the Chem. Toxicol. 2009, 47, 802-808. plant tissue colors (red, blue, [1] Malatya Kayısısı. T.C. Malatya and purple) and thus greatly Valiliği. http://www.malatya.gov. [10] Leccese, A.; Bartolini, S.; contribute to the visual quality tr/malatya-kayisisi- Viti, R. Total antioxidant capacity of the fruit [12]. Apricot also and phenolics content in apricot contains a reasonable amount [2] Ünal, M.; R. Kayısı Araştırma fruits. Int. J. Fruit Sci. 2007, 7, of dietary fiber ranging from Raporu, T.C. Fırat Kalkınma 3-16. 1.5 to 2.4 g/100 g on a fresh Ajansı, 2010. weight basis [13]. It also contains [11] Leccese, A.; Viti, R.; Bartolini, various amounts of essential [3] Akinci, M. B.; Olmez, H. S. The effect of solvent extraction minerals. The main elements are A. Kayısı. Malatya Tarım İl on antioxidant properties of potassium, phosphate, calcium, Müdürlüğü, Malatya, Turkey, apricot fruit. Central Eur. J. Biol. magnesium, iron, and selenium 2004. 2011, 6, 199-204. [14]. Sodium, manganese, zinc, and copper are also found in [4] Bilgin, N. A.; Mısırlı, A. Bazı [12] Mazza, G.; Miniati, E.

5 CATALYZER PAGE - 7 INTERNATIONAL CHEMISTRY OLYMPIAD MAGAZINE / ISTANBUL - TURKEY 2020 ©iStock

A Forensic Detector: Ninhydrin

Hamdullah Kılıç

Ninhydrin (Fig.iStock: 1; also 283712575known as 2,2-dihydroxyindane- 1,3-dione) reacts with primary and secondary amines Ninhydrin (Fig. 1; toalso give known a compound as 2,2 with-dihydroxyindane a deep blue or purple-1,3- dione)color reacts with primary known as Ruhemann’s purple. Thus, ninhydrin is a and secondary amines tochemical give a indicator compound to test with whether a deep or not blue a compound or purple color known as Ruhemann’s purple. Thus,has ninhydrinthe terminal isamine a chemical group. Ninhydrin indicator is a whiteto test solid whether or not a compound has the terminalwith amine a melting group point. Ninhydrin of 250 °C and is ais whitesoluble solid in polar with a melting point of solvents such as water, ethanol, and acetone at ambient 250 °C and is soluble intemperature. polar solvents such as water, ethanol, and acetone at ambient temperature.

A FORENSIC DETECTOR: FigureFigure 1. The 1. The structure structure of of ninhydrin ninhydrin and itsits hydrates hydrates form. form. How does ninhydrinHow help does forensic ninhydrin science help forensic in obtaining science in evidence obtaining for theft detection? Sildi: Fingerprints are composedevidence of water, for theftsalts, detection? lipids, vitaminsFingerprints, and are amino composed acids. Commercially Sildi: of water, salts, lipids, vitamins, and amino acids. NINHYDRIN Sildi: a piece of available visible stain theftCommercially detection kit availables contain visible ninhydrin stain theft, which detection is used kits to identify thieves Sildi: s Hamdullah Kılıç by applying it to any objectcontain that mayninhydrin, get stolen which. isWhen used toskin identify comes thieves into by contact with an object applying it to any object that may get stolen. When skin s marked with ninhydrin, the body's amino acids (Fig. 2) react with ninhydrin to create a very Sildi: comes into contact with an object marked with ninhydrin, the visible purple stain on the body lasting a few days. Sildi: Sildi: up to

PAGE - 8 Figure 2. General structure of amino acids. A Forensic Detector: Ninhydrin

Hamdullah Kılıç

iStock: 283712575 Ninhydrin (Fig. 1; also known as 2,2-dihydroxyindane-1,3-dione) reacts with primary and secondary amines to give a compound with a deep blue or purple color known as Ruhemann’s purple. Thus, ninhydrin is a chemical indicator to test whether or not a compound has the terminal amine group. Ninhydrin is a white solid with a melting point of 250 °C and is soluble in polar solvents such as water, ethanol, and acetone at ambient temperature.

Figure 1. The structure of ninhydrin and its hydrates form.

How does ninhydrin help forensic science in obtaining evidence for theft detection? Sildi: Fingerprints are composed of water, salts, lipids, vitamins, and amino acids. Commercially Sildi: available visible stain theft detection kits contain ninhydrin, which is used to identify thieves Sildi: a piece of by applying it to any object that may get stolen. When skin comes into contact with an object Sildi: s marked with ninhydrin, the body's amino acids (Fig. 2) react with ninhydrin to create a very Sildi: s Sildi: the visible purple stain on the bodythe body’s amino last acids (Fig.ing 2) react witha ninhydrinfew to create days a very visible. purple stain on the body lasting a few days. Sildi: up to

Figure 2. General structure of amino acids. Figure 2. General structure of amino acids. Now let us look at theNow chemistry let u behinds look ninhydrin. at the In the chemistry first step, ninhydrin behind is dehydratedninhydrin and. reactsIn the with firstan amino step, group ninhydrin of the amino isacid Sildi: ’ (except proline) to give an imine I. In the next step, decarboxylation from the imine I take place to give imine II. Then the imine II undergoes hydrolysisdehydrated with water, forming and an reacts aldehyde with and diketohydrindamine.an amino group of the amino acid (except proline) to give an Sildi: the imineNow I. In letthe u nexts look step, at decarboxylation the chemistry from behind the ninhydrin imine I take. In place the firstto give step, imine ninhydrin II. Then is Sildi:Sildi: chemistry ’ dehydratedthe imine andII undergoes reacts with hydrolysis an amino with groupwater , offorming the amino an aldehyde acid (except and diketohydrindamine. proline) to give an Sildi:Sildi: , the imine I. In the next step, decarboxylation from the imine I take place to give imine II. Then Sildi: chemistry the imine II undergoes hydrolysis with water, forming an aldehyde and diketohydrindamine. Sildi: ,

Finally, diketohydrindamine with primary amine moiety undergoes a condensation reaction Finally, diketohydrindaminewith ninhydrin with to primarygive a amine colored moiety product undergoes, which a condensation is called reaction Ruhemann’s with ninhydrin topurple. give a colored product, which is called Ruhemann’s purple. Finally, diketohydrindamine with primary amine moiety undergoes a condensation reaction with ninhydrin to give a colored product, which is called Ruhemann’s purple.

5 CATALYZER PAGE - 9 INTERNATIONAL CHEMISTRY OLYMPIAD MAGAZINE / ISTANBUL - TURKEY 2020

WHAT ARE BEHIND CUBES?

Have you ever tried solving a Rubik’s cube? Rubik’s cube, I patiently watched videos to I am sure you have and gave up working on learn the “Beginner’s Method” on YouTube. it after completing only one face. Although My first personal record without looking at you see Rubik’s cube solution exhibitions on the video was 5 minutes. I memorized only talent shows just as if the performers are a few algorithms and did a lot of practice. magicians, there is, of course, an algorith- Any progress? I improved my record to 1 mic way of explaining how they do it. minute. However, after that point, I realized that my record would not get better than As a Rubik’s cube solver from Turkey, I that. Consequently, I decided to improve my have been doing this as a hobby for 7 years. technique of the most famous speedcubing First of all, I saw one of my friends in mid- method, known as the Friedrich Method. dle school solving a Rubik’s cube within 5 This method has plenty of algorithms to be minutes after scrambling it. At that moment, memorized, yet instead of memorizing ev- my interest in Rubik’s cubes was born, and ery single notation, coding those algorithms so I did some quick research on the Internet into your fingers rather than your mind and found out that there were a few meth- consumes less time. Therefore, I developed ods to solve the cube. Because there are a way of enhancing my memory, which 43 quintillion combinations for a 3 × 3 × 3 assisted me in my academic and social life

PAGE - 10 since I was able to memorize everything move becomes your way of thinking, it makes ested in such an extreme hobby satisfies me much faster. Finally, my record was below 1 everything easier in your real life as well. a lot. minute as I had expected. I was aware of the fact that there were not To conclude, Rubik’s cubes entered my life 7 I started following popular Rubik’s cubers many Turkish online resources and so I years ago. However, my interest has never on social media, and so I found another di- created a YouTube channel called “MyCubes waned since then. It taught me a lot of things vision of speedcubing. Did you know that a AndI”, in which I shared tutorials about how and enhanced my performance in real life in Rubik’s cuber takes care of his/her puzzles to solve Rubik’s cubes and get prepared for many aspects. This entertainment may be like a baby? I watched lots of unboxing and competitions. Then I decided to share videos the most beneficial and interesting one in reviewing videos of different brands of Ru- of me solving puzzles in the other countries the world since you catch everybody’s eyes bik’s cubes to decide on my first professional I visit. Those moments are so special to me once you start doing it. So, if I were you I cube and ordered one. 50 seconds! After that, because many people gather around me would take the closest Rubik’s cube, it is the I met the Turkish delegate of the World Cube while I am solving the puzzle in front of a best-selling toy of all time and so I am sure Association (WCA), İskender Aznavur, and tourist attraction, scramble the puzzles, and there is one close to you, and learn how to learned that many competitions were being applaud me as I complete them. I even met solve it! held in one day all around the globe. Since I an old Rubik’s cuber in Barcelona and shot a Burak Alanyalioglu was fond of this hobby, I increased the num- video with him. Seeing how people get inter- ber of puzzles in my collection by learning how to solve 2 × 2 × 2 and Pyraminx puzzles. Can you believe that there is a puzzle in the shape of a pyramid? Just wait for the next ones! I attended the national competition in Istanbul and met a lot of speedcubers. It was a stunning day for me since everybody around me was speaking the language of Rubik’s cubes. Everyone was teaching and challenging each other. Although I competed in three categories, I witnessed all the categories. Blindfolded, one-handed, and Skewb categories were the most fascinating ones. In total, I took part in three different national competitions and in each of them I was so excited just like everyone else since sharing a common secret talent in an organization is superb.

Throughout all my experiences, I saw the impact of practicing a lot. My fingers got much stronger. Thus, I am now able to perform more than three moves per second, and I can use all of my fingers perfectly. In addition to that, when I tried learning blindfolded cube solving this process taught me a new aspect: 3-D thinking! Because I have to imagine all those next steps in my mind, I rotate the im- age of the Rubik’s cube in my mind. Further- more, this skill helped me even in science classes. It is very useful for me to imagine a 3-D model of a molecule in chemistry classes. As it was a hobby for me and had a lot of benefits, I was willing to widen my collection. Subsequently, I found the most extreme puzzles on the market such as the 7 × 7 × 7, gear cube, void cube, and 360 puzzles. By the way, some of these puzzles don’t have a method. Therefore, I developed my own strategies and challenged myself. Also, one of the most important things that improve your solutions is foreseeing the next move. I wholehearted- ly believe that when figuring out your next

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DIVRIGI GREAT MOSQUE AND HOSPITAL

Hüseyin YURTTAŞ

Esra HALICI

Burak Muhammet GÖKLER

Muhammed Emin DOĞAN

Located in the Divriği district of Sivas Province, the mosque was founded by the Mengüjek bey Ahmed Shah between 1228 and 1243; the hospital, on the other hand, was founded by Ahmed Shah’s wife Turan Melek between the same dates and designed by architect Hürrem Shah, son of Ahlatlı Muğis.

The design of the mosque involves a sanctuary section consisting of five naves and it is covered with 23 different vaults and two domes. The front of the mihrab is covered with a star- shaped cone on the outside and dominates the mosque from the outside. The mosque has three entrances with the qibla portal (north crown portal), the bazaar portal in the west, and the shah portal in the east.

The stone decoration created by the craftsmen from Ahlat was reflected differently on all three portals. These ornamentations

Divriği, Mosque - Decoration

Divriği, Turkey - located in Central Anatolia, Divriği is a popular tourist destination. Here in particular the Great Mosque, a UNESCO World Heritage site

are regarded as unprecedented and unique examples in Anatolia, Built on the south wall of the mosque, the hospital consists of three both in size and magnificence. The distinctive feature of Divriği Great iwans, the central part of which is covered with a skylight dome. A Mosque and Hospital is that many motifs seem symmetrical but are tomb is located in the northeast corner of the hospital. The crown actually asymmetrical and do not repeat each other. In addition, the portal of the building is monumental like the northern crown gate of double-headed eagle, which is considered to be the coat of arms of the mosque but has a different design. Both male and female heads Alaaddin Keykubad, and the figures of Ahmed Shah’s coat of arms, are embossed on both sides of the entrance door. were carved into the western crown portal. Divriği Great Mosque and Hospital was added to the UNESCO World Heritage List in 1985.

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Problem 5.

Alaaddin is trapped in a dark cave. In order to escape he should activate his enchanted lamp. He knows that if one simultaneously puts two magic sticks into the enchanted lamp then it will be activated and the gates of the cave will immediately open. There are 200 indistinguishable sticks and exactly 100 of them are magic. In each trial Alaaddin puts two sticks into the enchanted lamp. Determine the smallest possible value of n if Alaaddin can guarantee to activate the enchanted lamp in at most n trials.

Azer Kerimov

Answer of yesterday’s problem :

There are at most 8 paintings in the exhibition.

Let us denote the colors by 1, 2,...,8. The collection of paintings colored by colors (1,2,3), (1,4,5), (1,6,7), (2,6,8), (3,4,8), (5,7,8), (3,5,6), (2,4,7) is an example for 8 paintings.

Now let us show that the number of paintings is at most 8. Let us fix a color c. Each of the remaining 7 colors can be used with c only in one painting. Therefore, the color c is used in at most 3 paintings and the total number of used colors is at most 8 ∙ 3 = 24. Therefore, there are at most 8 paintings in the exhibition.

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CHINA

Theoretical knowledge exam of the Chinese Chemistry Olympiad

NEWS FROM NATIONAL TEAMS OF COUNTRIES

PAGE - 16 ECUADOR

National Ecuadorian Competitions

5 CATALYZER PAGE - 17 INTERNATIONAL CHEMISTRY OLYMPIAD MAGAZINE / ISTANBUL - TURKEY 2020

ELSALVADOR

Participants of El Salvador

PAGE - 18 HUNGARY

MS Teams exam all over Hungary

5 CATALYZER PAGE - 19 Sponsors Graphic-Design English Editor Advisory Board Editor Publisher ©iStock InternationalUnion ofPure andAppliedChemistry, IUPAC InternationalChemistryOlympiad JapanCommittee, Japan Chemical SocietyLocated in Taipei, China : American Chemical Society, USA : Prosigma Inc, Ankara, Turkey. |www.prosigma.net : Russell Fraser : ArifDaştan, Nurullah Saraçaoğlu, ÖzlemKılıçEkici : HasanSeçen : Scientificand Technological Research Councilof Turkey