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MedicinalChemistry

Mechanism of

Procarbazine

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SitiNursayyidah 260110100160

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Prokarbazine:

ObatGolongansenyawapengalkilasigolongan

hydrazineMekanisme Metabolisme :

1. Senyawa pengalkilasi dapat membentuk senyawa kationik antara yang tidak stabil,diikuti pemecahan cincin membentuk ion karbonium reaktif.

2. Ion tersebut bereaksi, melalui reaksi alkilasi, membentuk ikatan kovalen dengan

gugus-gugus donor elektron (seperti gugus karboksilat, amin, fosfat dan tiol yangterdapat pada struktur asam amino, asam nukleat dan protein yang sangatdibutuhkan untuk proses biositesis sel)

3. Reaksi ini membentuk hubungan melintang (cross-linking) antara dua rangkaianDNA dan mencegah mitosis. Akibatnya proses pembentukan sel terganggu anterjadi hambatan pertumbuhan sel kanker

1. Pembentu kan

metabo l i t akt i f

[mety lazoxyprocarbazine]

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Hydrazine Hydrazine (also called diazane) is aninorganic compound with the formulaN2H4

Azoxy Azoxy compounds are a group ofchemical compounds sharing a commonfunctional group with the generalstructure RN=N+(O

). They are

considered N-oxides of azo compounds.Azoxy compounds are 1,3-dipoles. Theygive 1,3 dipolar cycloaddition with doublebonds.Azoxy compounds are suspected to begenotoxic

1. Pembentu kan

metabo l i t akt i f

[mety lazoxyprocarba

zine](2)

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Senyawa turunan hidrazin yang dengan adanya metaloprotein akan teroksidasi menjadi

azoprokarbazin, diikuti dengan terbentuknya isomer hidrazon. Isomer tersebut akan

terhidrolisisi menjadi p-formil-N-Isopropilbenamide dan metil hidrazine. Metil hidrazine

kemudian teroksidasi menjadi metil diazine, yang segera mengalami peruraian menjadi

nitrogen, radikal metil dan radikal hidrogen.

1. Pembentu kan

metabo l i t akt i f

[metylazoxyprocarbazi

ne](3)

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Metalloprotein?

Thestructureofhemoglobin.Thehemecofactor,containing

iron,Metalloproteinisagenerictermforaproteinthatcontains

ametalioncofactor.Alargefractionofallproteinsaremembersofthiscategory,sotheareaisverylarge.

Metalloproteinsarewidespreadanddiverseinfunction,Itis

estimatedthatapproximatelyhalfofallproteinscontaina

metal.Inanotherestimate,aboutonequartertoonethirdofall

proteinsareproposedtorequiremetalstocarryouttheir

functions.Thus,metalloproteinshavemanydifferentfunctions

incells,suchasstorageandtransportofproteins,enzymes

andsignaltransductionproteins.

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1. Pembentukan metabo l i t

akti f

[metylazoxyprocarbazine]. .

(4) sebagai an tikanker

The primary enzymatic oxidation product,azo-procarbazine,was also not effective.

Only exposure of the cells to either of the twoazoxy isomers of procarbazine (the metabolicproducts of azo-procarbazine) led to

significant amounts of concentration-,temperature-, and time-dependent DNAdamage.

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The subsequent

conversion of azo-PCZ tothe two isomerie azoxyderivatives has been shownto be catalyzed exclusively

by cytochrome P-450 Themetabolism of the azoxymetabolites of either 1,2-dimethylhydrazine or PCZ(Fig. 1) has been suggested

to be a final step involvedin the metabolic activationof these two 1,2-disubstituted hydrazines

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Pembentuk an senyawa

radikal dari

metylazoxyprocarbazin

e [ ion mety lkarbonium ]

Isomer hidrazon akan terhidrolisis atau pecah membentuk dua senyawa

yaitu menjadi p-formil-N-isopropilbenzamid dan metilhidrazi

CH3NHNH2 +

meti lh idrazin p-formi l -N- isopropi lbenzamid

azoprocarbazine isomer hidrazone

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metilhidrazininiteroksidasimembentuk

metildiazin.Padaprosesoksidasiini,

terjadipelepasanatomHpadasenyawametilhidrazin

CH3NHNH2 CH3N=NH

metilhi r zin metil i zin

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Metildiazinyangterbentukakan

mengalamiperuraianmenjadiion

methyldiazoniumdanradikalhydrogen

dan senyawa radikal *H (hydrogen)

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Metildiazoniumtersebutakansegeramengalamiperuraianmenjadinitrogendansenyawaradikalmetil

Radikalbebasmetil[ionmethyldiazonium]inimerupakanagenpengalkilasiyangberinteraksidenganARNpaadasitoplasmasel

*N2 + CH3

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ProfilProcarbazine

berdasarkanQSAR

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Proses

Pembentukan

Radikal

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Proses

Pembentukan

Radikal

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Commonly used combination for procarbazine MOPP:Mechlorethamine,vincristine(oncovin),procarbazine,prednisone

PCV: Procarbazine,lomustine,vincristine

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Theoralagentprocarbazineisamethylhydrazinederivative,

anditiscommonlyusedincombinationregimensfor

Hodgkin'sdisease,non-Hodgkin'slymphoma,andbrain

tumors.Thedrugisalsoleukemogenicandhasteratogenicandmutagenicproperties.Themechanismofactionof

procarbazineisuncertain;however,thedruginhibitsthe

synthesisofDNA,RNA,andprotein;prolongsinterphase;

andproduceschromosomebreaks.Oxidativemetabolismofthisdrugbymicrosomalenzymesgenerates

azoprocarbazineandH2O2,whichmayberesponsiblefor

DNAstrandscission.

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Alkylatingagentsarecompoundsthatarecapableof

introducinganalkylgroupintonucleophilicsitesonDNA,

RNAoranyenzymethroughcovalentbond.

Theseagentsarethoughttoreactwiththe7positionofguanine(oranyothernitrogenbase)ineachofthedouble

strandsofDNA,causingcross-linkingthatinterfereswith

separationofthestrandsandpreventsmitosis.

TheeffectsofbasealkylationincludemisreadingoftheDNAcodonandsinglestrandbreakageoftheDNAchain.

However,thelongtimeeffectsaremutationandcelldeath.

ThefavoredsiteonDNAisattheN7positionofguanine,

adenine,cytosine,andeventhesugarphosphategroups.

Common

alky lat ing agen t

mechanism:

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Procarbazine(N-isopropyl-4-[(2-methylhydrazino)methyl]benzamide)

Itmustbeconvertedintoanazoderivativeinvivoto

becomeactiveagainsttumorcells.

AlkylationofDNAorpossibletransmethylationmaybethe

modeofaction.

ItisacomponentoftheMOPP(Mechlorethamine,

vincristine,procarbazineandpredinsone)combinationthatissoeffectiveintreatmentofHodgkinsdisease.

Ithasmonamineoxidaseinhibitionproperties(MAOI),So

itshouldnotbetakenwithmostantidepressantsand

certainmigrainemedications.

Speci f ic Mechanism for

Methylhydrazines

(Procarbazine)

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