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Reactions of Model and Anticancer Active Platinum(IV/II) Complexes - A Kinetic and Mechanistic Study

Lemma, Kelemu LU (2001)
Abstract
In this thesis reductions of model and anticancer active Pt(IV) complexes with thiols and ascorbic acid and substitution reactions of cisplatin and model Pt(II) complexes with S-donor nucleophiles (rescue agents) have been investigated using stopped-flow and UV/VIS spectrophotometry. Glutathione (GSH) reduction of the anticancer active Pt(IV) compounds t- and c-[PtCl4(cha)(NH3)] (cha = cyclohexylamine), t-[PtCl4(thiazole)(NH3)] and c-[PtCl4(NH3)2] at 25 oC was observed to be very fast. Thiol reduction of the non-classical Pt(IV) compound t,t,t-[PtCl2(OH)2(cha)(NH3)] (JM335) at 25 oC and pH > 7 is moderately rapid while the cis isomer c,t,c-[PtCl2(OH)2(cha)(NH3)] (JM149) is not reduced. Ascorbate (Asc2-) reduction of the orally active... (More)
In this thesis reductions of model and anticancer active Pt(IV) complexes with thiols and ascorbic acid and substitution reactions of cisplatin and model Pt(II) complexes with S-donor nucleophiles (rescue agents) have been investigated using stopped-flow and UV/VIS spectrophotometry. Glutathione (GSH) reduction of the anticancer active Pt(IV) compounds t- and c-[PtCl4(cha)(NH3)] (cha = cyclohexylamine), t-[PtCl4(thiazole)(NH3)] and c-[PtCl4(NH3)2] at 25 oC was observed to be very fast. Thiol reduction of the non-classical Pt(IV) compound t,t,t-[PtCl2(OH)2(cha)(NH3)] (JM335) at 25 oC and pH > 7 is moderately rapid while the cis isomer c,t,c-[PtCl2(OH)2(cha)(NH3)] (JM149) is not reduced. Ascorbate (Asc2-) reduction of the orally active Pt(IV) compounds c,t,c-[PtCl2(OCOCH3)2(cha)(NH3)] (JM216) and c,t,c-[PtCl2(OCOC3H7)2(cha)(NH3)] (JM221) at near neutral pH and 35 oC is relatively slow. All the electron transfer reactions follow the rate law: -d[Pt(IV)]/dt = k [Pt(IV)] [RA]tot where k denotes a pH-dependent second-order overall rate constant and [RA]tot the total concentration of reducing agent. Thiol and ascorbate reductions of the Pt(IV) complexes containing an X-PtIV-X (X = Cl, Br) axis is suggested to proceed via a halide-bridged two-electron transfer mechanism. Ascorbate reduction of JM216 and JM221, where the chlorides are co-ordinated trans to cyclohexylamine and NH3, is proposed to follow an outer-sphere mechanism. The observed reduction reactions support the assumption that anticancer active Pt(IV) compounds require reduction to their Pt(II) counterparts before binding to the pharmacological target, DNA. Among others, glutathione and ascorbic acid are assumed to be the potential reducing agents in the body. It is concluded that Pt(IV) compounds with high rates of reduction cannot be expected to display improved activity compared to their Pt(II) analogues. The chemoprotective agents diethyldithiocarbamate (DDTC), thiosulfate, thiourea, GSH, 2-mercaptoethanesulfonate (mesna), and 2-mercaptoethylamine display a comparable reactivity towards the model complex [Pt(dien)Cl]+. DDTC was observed to be the most reactive nucleophile consistent with the report that it is the only rescue agent effective when administered after cisplatin. It is suggested that the rest of the rescue agents investigated can be expected to have the same mechanism of renal protection, although their transport and tissue distribution properties could also play a role. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Den kemiskt enkla föreningen cis-[PtCl2(NH3)2)] (cisplatin) används för behandling av vissa cancerformer. Föreningen är i allmänhet giftig för kroppens organ och kroppen utvecklar resistens, vilket begränsar den kliniska effektiviteten. Generellt anses det att den önskade anticancer-effekten fås som ett resultat av inbindningen av platinakomplexen till DNA, medan interaktioner med andra biomolekyler, t.ex. proteiner, är orsaken till oönskade och giftiga sidoeffekter. Minskat upptag, ökad avgiftning av cytoplasman och ökad kapacitet hos cellerna att avlägsna platina-DNA-komplex antas vara orsakerna bakom kroppens resistens mot platinakomplexen. En s.k. andra-generationens substans är carboplatin... (More)
Popular Abstract in Swedish

Den kemiskt enkla föreningen cis-[PtCl2(NH3)2)] (cisplatin) används för behandling av vissa cancerformer. Föreningen är i allmänhet giftig för kroppens organ och kroppen utvecklar resistens, vilket begränsar den kliniska effektiviteten. Generellt anses det att den önskade anticancer-effekten fås som ett resultat av inbindningen av platinakomplexen till DNA, medan interaktioner med andra biomolekyler, t.ex. proteiner, är orsaken till oönskade och giftiga sidoeffekter. Minskat upptag, ökad avgiftning av cytoplasman och ökad kapacitet hos cellerna att avlägsna platina-DNA-komplex antas vara orsakerna bakom kroppens resistens mot platinakomplexen. En s.k. andra-generationens substans är carboplatin ([Pt(CBDA)-(NH3)2], CBDA = 1,1-cyclobutandikarboxylat) vilken primärt används då det är nödvändigt att minimera de giftiga sidoeffekter som cisplatin orsa-kar. Det är också möjligt att ge svavelinnehållande ämnen, s.k. "rescue agents", på samma gång som man ger cisplatin, för att lindra de giftiga sidoeffekterna. I denna avhandling har en kvantitativ studie av hastighe-terna för reaktioner mellan några sådana ämnen och olika platina(II)kom-plex genomförts. Kunskap om reaktionshastigheten och tillhörande parametrar är viktig för att förstå hur de verkar och för framtagande av nya mer selektiva substanser. Resistens mot platinaföreningarna kan kringgås om steriskt hindrande bärarligander, t.ex. 1,2-trans-diaminocyklohexan (dach) och nya sorters platinakomplex används. Ett exempel på ett komplex med steriskt hindrande bärarligander är platina(IV)komplexet trans,trans,trans-[PtCl2(OH)2(cha)(NH3)] (JM335) (cha = cyklohexyl-amin). Det har visat sig vara effektivt mot vissa cisplatinresistenta celler, där resistensen i huvudsak berott på antingen minskad ansamling av platinakomplex, på ökad bortföring eller på ökad tolerans mot platina-DNA-komplex. Eftersom både cisplatin och carboplatin måste ges intravenöst undersöks möjligheterna att hitta preparat som kan ges oralt. Detta har gjorts oberoende av de utvecklingsprogram som har varit ämnade att ta fram andra- och tredjegenerationens preparat. Blandade aminplatina(IV)-dikarboxylatkomplex har befunnits vara lämpliga att ge oralt, eftersom de reagerar långsamt, är syretåliga och lipofila. JM216, cis,trans,cis--[PtCl2(OCOCH3)2(cha)(NH3)], är det första av denna sorts komplex. För att binda in till DNA antas de anticanceraktiva platina(IV)kom-plexen reduceras i kroppen till de mer reaktiva platina(II)-analogerna. I denna avhandling har dessa redoxreaktioner studerats genom att använda anticanceraktiva platina(IV)komplex eller modeller för sådana med tioler och askorbinsyra som reduktionsmedel. Tetrakloroplatina(IV)föreningar reduceras mycket fort av glutation (GSH), vilket tyder på att anticancer-aktiviteten hos dessa föreningar inte är helt olik den för motsvarande platina(II)komplex. Däremot reduceras JM335 relativt långsamt av tioler, under det att cis-isomeren, cis,trans,cis--[PtCl2(OH)2(cha)(NH3)] (JM149), inte påverkas alls. Reduktion av JM216 och 221, cis,trans,cis-[PtCl2(OCOC3H7)2(cha)-(NH3)], med askorbinsyra vid neutralt pH och 35 *C sker ännu långsammare. Resultaten som presenteras i avhandlingen visar att redoxreaktiviteten är en viktig faktor som påverkar anticancer-aktiviteten hos platina(IV)komplexen. För att uppnå det bästa upptaget och fördelningen måste reduktionen av platina(IV)komplexen till de mer reaktiva platina(II)komplexen ske med lämplig hastighet. (Övers: Johan Kjellström) (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Natile, Giovanni, Dipartimento Farmaco-Chimico, Universita Via E. Orabona 4, I-70125 Bari, Italy
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Model Pt(II) complexes, Anticancer active Pt(IV) compounds, Cisplatin, Rescue agents, L-Ascorbic acid, Thiol, Substitution, Kinetics and mechanism, Electron transfer, Inorganic chemistry, Oorganisk kemi
pages
122 pages
publisher
Inorganic Chemistry, Chemical Center, Lund University
defense location
Chemical Center, Sölvegatan 39, Hall E
defense date
2001-11-02 10:15:00
ISBN
91-628-5002-4
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Inorganic chemistry (ceased) (LUR000010)
id
4eae11f2-9b71-4f9d-b29f-01d07b77916e (old id 41998)
date added to LUP
2016-04-04 10:18:12
date last changed
2018-11-21 20:58:00
@phdthesis{4eae11f2-9b71-4f9d-b29f-01d07b77916e,
  abstract     = {{In this thesis reductions of model and anticancer active Pt(IV) complexes with thiols and ascorbic acid and substitution reactions of cisplatin and model Pt(II) complexes with S-donor nucleophiles (rescue agents) have been investigated using stopped-flow and UV/VIS spectrophotometry. Glutathione (GSH) reduction of the anticancer active Pt(IV) compounds t- and c-[PtCl4(cha)(NH3)] (cha = cyclohexylamine), t-[PtCl4(thiazole)(NH3)] and c-[PtCl4(NH3)2] at 25 oC was observed to be very fast. Thiol reduction of the non-classical Pt(IV) compound t,t,t-[PtCl2(OH)2(cha)(NH3)] (JM335) at 25 oC and pH > 7 is moderately rapid while the cis isomer c,t,c-[PtCl2(OH)2(cha)(NH3)] (JM149) is not reduced. Ascorbate (Asc2-) reduction of the orally active Pt(IV) compounds c,t,c-[PtCl2(OCOCH3)2(cha)(NH3)] (JM216) and c,t,c-[PtCl2(OCOC3H7)2(cha)(NH3)] (JM221) at near neutral pH and 35 oC is relatively slow. All the electron transfer reactions follow the rate law: -d[Pt(IV)]/dt = k [Pt(IV)] [RA]tot where k denotes a pH-dependent second-order overall rate constant and [RA]tot the total concentration of reducing agent. Thiol and ascorbate reductions of the Pt(IV) complexes containing an X-PtIV-X (X = Cl, Br) axis is suggested to proceed via a halide-bridged two-electron transfer mechanism. Ascorbate reduction of JM216 and JM221, where the chlorides are co-ordinated trans to cyclohexylamine and NH3, is proposed to follow an outer-sphere mechanism. The observed reduction reactions support the assumption that anticancer active Pt(IV) compounds require reduction to their Pt(II) counterparts before binding to the pharmacological target, DNA. Among others, glutathione and ascorbic acid are assumed to be the potential reducing agents in the body. It is concluded that Pt(IV) compounds with high rates of reduction cannot be expected to display improved activity compared to their Pt(II) analogues. The chemoprotective agents diethyldithiocarbamate (DDTC), thiosulfate, thiourea, GSH, 2-mercaptoethanesulfonate (mesna), and 2-mercaptoethylamine display a comparable reactivity towards the model complex [Pt(dien)Cl]+. DDTC was observed to be the most reactive nucleophile consistent with the report that it is the only rescue agent effective when administered after cisplatin. It is suggested that the rest of the rescue agents investigated can be expected to have the same mechanism of renal protection, although their transport and tissue distribution properties could also play a role.}},
  author       = {{Lemma, Kelemu}},
  isbn         = {{91-628-5002-4}},
  keywords     = {{Model Pt(II) complexes; Anticancer active Pt(IV) compounds; Cisplatin; Rescue agents; L-Ascorbic acid; Thiol; Substitution; Kinetics and mechanism; Electron transfer; Inorganic chemistry; Oorganisk kemi}},
  language     = {{eng}},
  publisher    = {{Inorganic Chemistry, Chemical Center, Lund University}},
  school       = {{Lund University}},
  title        = {{Reactions of Model and Anticancer Active Platinum(IV/II) Complexes - A Kinetic and Mechanistic Study}},
  year         = {{2001}},
}