Synthesis and Antimalarial Activity of Novel Medium-Sized 1,2,4,5-Tetraoxacycloalkanes

Kim, Hyesook; Nagai, Yukiko; Ono, Kanako; Begum, Khurshida; Wataya, Yusuke; Hamada, Yoshiaki; Tsuchiya, Kousuke; Masuyama, Araki; Nojima, Màsatomo; McCullough, Kevin J.

doi:10.1021/jm010026g

Cited by 127 publications

(104 citation statements)

References 10 publications

(15 reference statements)

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“…Furthermore, we analyzed the sequence of the pfcrt gene of the FCR-3 strain, which has recently been shown to potentially be involved in chloroquine resistance. As a result, the FCR-3 strain shows no mutation (K76, chloroquine sensitive), but the K1 strain has a mutation (T76, chloroquine resistant) (unpublished data) as previously described (Kim et al , 2001. In brief, the antimalarial activity was assessed by incubating parasite cultures at 0.3% of the initial parasitemia with the metalloporphyrins for 72 h in an incubator (5% O 2 , 5% CO 2 and 90% N 2 atmosphere).…”

Section: Methodsmentioning

confidence: 97%

“…The IC 50 value represents the amount of the compound required to inhibit the increase in parasite density at 72 h after incubation by 50% of the control. Cytotoxicity against mouse mammary tumor cells was determined by incubating FM3A cells with diluted compounds for 48 h as described previously (Kim et al , 2001. Synchronization was maintained using 5% (w/v) sorbitol (Lambros and Vanderberg 1979) and the trophozoite lysate of P. falciparum was prepared according to the procedures of Dorn et al (1995).…”

Section: Methodsmentioning

confidence: 99%

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In vitro antimalarial activity of metalloporphyrins against Plasmodium falciparum

et al. 2003

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The in vitro antimalarial activity against Plasmodium falciparum and heme polymerization were evaluated for ten metalloporphyrins: gallium protoporphyrin IX (GaPPIX), sodium salt of gallium protoporphyrin IX, silver protoporphyrin IX, palladium protoporphyrin IX, cobalt protoporphyrin IX, manganese protoporphyrin IX, tin protoporphyrin IX (SnPPIX), chromium protoporphyrin IX, gallium deuteroporphyrin IX (GaDPIX) and gallium hematoporphyrin IX. Metalloporphyrins inhibited parasite growth with 50% inhibitory concentrations (IC(50)) ranging from 15.5 microM to 190 microM. In trophozoite lysate-mediated heme polymerization assays, SnPPIX, GaPPIX and GaDPIX exerted potent inhibitory activity similar to that of artemisinin and chloroquine.

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Section: Methodsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

In vitro antimalarial activity of metalloporphyrins against Plasmodium falciparum

et al. 2003

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“…A series of novel achiral spiro 1,2,4,5-tetraoxocanes 47 were synthesized by CsOH-or Ag 2 O-mediated bis-alkylation (1,n-dihaloalkanes, n ¼ 3-8) of gem-dihydroperoxides obtained from ozonolysis of the corresponding vinyl ethers. 104,105 As illustrated by 47a and 47b, the in vitro potency of these spiro tetraoxocanes was excellent; 47a was in the same potency range as 1, 2a, and 2b. Both 47a and 47b, however, were an order of magnitude less effective than the artemisinins in vivo.…”

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confidence: 91%

“…All infected mice treated with 47b (p.o., 160 mg/kg/day, 3 days) were cured; using the same dosing regimen, none of the infected mice treated with 1 were cured. 105 Several hydroxy, methoxy, and iodine functionalized analogs of 47b, prepared from unsaturated hydroperoxy peracetals by ozonolysis followed by treatment with bis(sym-collidine)iodine(I) hexafluorophosphate, were 4-fold less potent than 47b.…”

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Synthetic peroxides as antimalarials

Tang

Dong²,

Vennerstrom³

2004

Medicinal Research Reviews

258

123

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The discovery of artemisinin in 1971 initiated a new era in antimalarial chemotherapy. Although the clinically useful semisynthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have short half-lives and must be administered over a period of 5-7 days, leading to noncompliance and recrudescence. With this in view, many synthetic antimalarial peroxides have been prepared. Yet, identification of orally active synthetic peroxide drug development candidates that are easily synthesized, inexpensive, and with good biopharmaceutical properties has been surprisingly difficult. In this review, we document the pitfalls and progress made in this endeavor. For each of 15 synthetic peroxide structural classes, we note highlights of the synthetic routes, product stereochemistry, and origin of the peroxide O atoms. Both in vitro and in vivo antimalarial data are then discussed and any SAR noted. Available data indicates that several synthetic 1,2,4-trioxanes are only marginally less effective than the semisynthetic artemisinins. Within a given peroxide chemical family, the more lipophilic members are more potent and possess better oral antimalarial activity in animal models than their more polar counterparts. This poses a challenge to identify peroxide structures with suitable "drug-like" physicochemical properties. Nonetheless, substantial progress has been made in the identification of a new generation of synthetic antimalarial peroxides.

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“…Od tada objavljeni su brojni naučni radovi i za nešto više od 250 tetraoksana je određena antimalarijska aktivnost (do 2009. godine) i utvrđeno je da neka od jedinjenja imaju snažnu in vivo antimalarijsku aktivnost (24,25).…”

Section: Slika 1-2 Najčešće Korišćeni Antimalariciunclassified

Antitumor effect of steroidal tetraoxanes on malignantly transformed human cell lines

Žižak¹

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Za CiuANTITUMORSKI EFEKAT STEROIDNIH TETRAOKSANA NA MALIGNO TRANSFORMISANE ĆELIJSKE LINIJEČOVEKA REZIME Uvod: Pronalaženje agenasa sa potencijalnim antitumorskim dejstvom je imperativ u modernoj onkologiji. Pri tome se sve više zapaža da određene hemijske strukture imaju specifičnije toksično dejstvo na maligne ćelije. Otkriće artemizinina je označilo početak istraživanja peroksida kao potencijalne zamene za tradicionalne antimalarijske lekove, a iz ovih istraživanja nastala je i strukturno jednostavna klasa peroksida -1,2,4,5-tetraoksani, za koje je ubrzo pokazano da pored antimalarijskog pokazuju i snažan antiproliferativni efekat. Maligne ćelije imaju poremećaje u regulatornim mehanizmima koji upravljaju ćelijskom proliferacijom i homeostazom. Sposobnost tumorskih ćelijskih populacija da povećaju broj ćelija je određena ne samo intenzitetom ćelijske proliferacije, već i brzinom uklanjanja ćelija. Programirana ćelijska smrt -apoptoza, predstavlja glavni izvor ovog uklanjanja.Cilj rada je bio da se odredi nivo citotoksičnog dejstva grupe mešovitih tetraoksana prema različitim humanim malignim ćelijama, kao i da se odredi koeficijenat selektivnosti u njihovom dejstvu u odnosu na zdrave imunokompetentne ćelije. U cilju dobijanja uvida u mehanizam dejstva ispitivanih jedinjenja odrediće se tip ćelijske smrti koju indukuju ispitivani tetraoksani, kao i produkcija reaktivnih kiseoničnih vrsta u Hela ćelijama. Cilj 3D QSAR studije o antiproliferativoj aktivnosti trideset tri 1,2,4,5-tetraoksanska derivata prema Hela i Fem-x tumorskim ćelijskim linijama, je bio da se utvrdi koje su najvažnije farmakofore steroidnih tetraoksana koje utiču na potenciju ispitivanih jedinjenja prema HeLa i Fem-x tumorskim ćelijskim linijama. Materijal i metode:Citotoksično dejstvo tetraoksana DO-122 -DO-124 i DO-126 -DO-128, prema pet tumorskih ćelijskih linija je ispitivano standardnim MTT testom. U cilju određivanja tipa ćelijske smrti indukovane tretmanom ispitivanim tetraoksanima načinjena je morfološka analiza HeLa ćelija obojenih smešom akridin oranža i etidijum bromida. Analiza određivanja distribucije faza ćelijskog ciklusa HeLa ćelija obojenih propidijum jodidom, urađena je na protočnom citometru. Produkcija intraćelijskih reaktivnih vrsta kiseonika (ROS) je merena fluorometrijski pomoću fluorescentne boje 2',7'-dihlorodihidrofluorescein diacetata. Zavisnost strukture i funkcije trideset tri 1,2,4,5-tetraoksanskih derivata prema HeLa i Fem-x ćelijskim linijama pokazana je 3D QSAR studijom. Rezultati:Ispitivani tetraoksani pokazuju dozno-zavisnu antiproliferativnu aktivnost u mikromolarnim koncentracijama prema ciljnim tumorskim ćelijama, uz dobru selektivnost u aktivnosti prema tumorskim ćelijama, u odnosu na normalne imunokompetentne ćelije. 24-časovni tretman HeLa ćelija sa svim ispitivanim tetraoksanima indukuju tipične morfološke karakteristike kasne apoptoze (kondenzovana i/ili fragmentisana jedra). Posle 24 i 48 časova inkubacije sa tetraoksanima, broj HeLa ćelija u G1 fazi se značajno uvećava. Nakon tretmana HeLa ćelija is...

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Synthesis and Antimalarial Activity of Novel Medium-Sized 1,2,4,5-Tetraoxacycloalkanes

Cited by 127 publications

References 10 publications

In vitro antimalarial activity of metalloporphyrins against Plasmodium falciparum

In vitro antimalarial activity of metalloporphyrins against Plasmodium falciparum

Synthetic peroxides as antimalarials

Antitumor effect of steroidal tetraoxanes on malignantly transformed human cell lines

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