Analysis of stereoelectronic properties of camptothecin analogues in relation to biological activity

Werbovetz, Karl A.; Bhattacharjee, Apurba K.; Brendle, James J.; Scovill, John P.

doi:10.1016/s0968-0896(00)00111-5

Cited by 30 publications

(19 citation statements)

References 16 publications

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“…From the activities observed ( Table 1) and those reported for cryptodorine (10), nornantenine (11) and xylopine (12) [1], we found the highest antileishmanial activity for alkaloids with two methylenedioxy functionalities (4 : 15 mM and 10 : 3 mM). Similar trends have been observed previously for other methylenedioxy compounds tested against different human diseases [3], [4], including several camptothecin analogues tested in Leishmania donovani [5]. The replacement of methylenedioxy functionalities with either hydroxy or methoxy moieties leads to a significant decrease in activity (5 : 210 mM; 6 : 395 mM; 7: > 916 mM and 8: > 916 mM).…”

supporting

confidence: 84%

Minor Alkaloids FromGuatteria dumetorumwith Antileishmanial Activity

Correa

Ríos

Castillo³

et al. 2006

Planta Med

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Nine known alkaloids [(+)-isodomesticine (1), (+)-norisodomesticine (2), (+)-nantenine ( 3), (+)-neolitsine (4), (+)-lirioferine (5), (+)-N-methyllaurotetanine (6), (+)-norlirioferine (7), (+)-isoboldine (8) and (+)-reticuline (9)] were isolated from young leaves of Guatteria dumetorum. Their structures were confirmed by NMR, mass and UV spectral analysis and by comparison to literature data. The growth inhibitory activity of each alkaloid was determined against the parasite Leishmania mexicana. Compounds 1-4 all showed significant activity whereby potency increased when a methylenedioxy functionality was present, especially at the 1,2-positions.

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supporting

confidence: 84%

Minor Alkaloids FromGuatteria dumetorumwith Antileishmanial Activity

Correa

Ríos

Castillo³

et al. 2006

Planta Med

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“…Another modification that improved the activity was the addition of the methylenedioxy group ( 2d ). This group has demonstrated the ability to potentiate the activity of triazole compounds [ 32 ], analogs of camptothecin [ 33 ], thiosemicarbazones [ 34 ] and secondary metabolites isolated from the stem bark of Rollinia emarginata [ 35 ]. We verified this potential in the phenotypic trials on L. amazonensis and L. braziliensis ; however, this effect was not seen in promastigotes of L.infantum .…”

Section: Discussionmentioning

confidence: 99%

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

Faiões

Frota

Cunha-Júnior

et al. 2018

J Venom Anim Toxins Incl Trop Dis

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BackgroundDespite the development of new therapies for leishmaniasis, among the 200 countries or territories reporting to the WHO, 87 were identified as endemic for Tegumentary Leishmaniasis and 75 as endemic for Visceral Leishmaniasis. The identification of antileishmanial drug candidates is essential to fill the drug discovery pipeline for leishmaniasis. In the hit molecule LQB-118 selected, the first generation of pterocarpanquinones was effective and safe against experimental visceral and cutaneous leishmaniasis via oral delivery. In this paper, we report the synthesis and antileishmanial activity of the second generation of pterocarpanoquinones.MethodsThe second generation of pterocarpanquinones 2a-f was prepared through a palladium-catalyzed oxyarylation of dihydronaphtalen and chromens with iodolawsone, easily prepared by iodination of lawsone. The spectrum of antileishmanial activity was evaluated in promastigotes and intracellular amastigotes of L. amazonensis, L. braziliensis, and L. infantum. Toxicity was assessed in peritoneal macrophages and selective index calculated by CC50/IC50. Oxidative stress was measured by intracellular ROS levels and mitochondrial membrane potential in treated cells.ResultsIn this work, we answered two pertinent questions about the structure of the first-generation pterocarpanquinones: the configuration and positions of rings B (pyran) and C (furan) and the presence of oxygen in the B ring. When rings B and C are exchanged, we noted an improvement of the activity against promastigotes and amastigotes of L. amazonensis and promastigotes of L. infantum. As to the oxygen in ring B of the new generation, we observed that the oxygenated compound 2b is approximately twice as active against L. braziliensis promastigotes than its deoxy derivative 2a. Another modification that improved the activity was the addition of the methylenedioxy group. A variation in the susceptibility among species was evident in the clinically relevant form of the parasite, the intracellular amastigote. L. amazonensis was the species most susceptible to novel derivatives, whilst L. infantum was resistant to most of them. The pterocarpanoquinones (2b and 2c) that possess the oxygen atom in ring B showed induction of increased ROS production.ConclusionsThe data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents.

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“…donovani promastigotes with an IC 50 value of 3.2 µM [122]. However, given the potent mammalian cytotoxicity of camptothecin and its analogues, it is doubtful that these compounds will serve as antileishmanial drug candidates [123]. Camptothecin was also toxic to T. brucei and T. cruzi in vitro, with EC 50 values of 1.5 and 1.6 µM, respectively.…”

Section: Indole Alkaloidsmentioning

confidence: 99%

Natural Products from Plants as Drug Candidates and Lead Compounds Against Leishmaniasis and Trypanosomiasis

Salem

Werbovetz²

2006

CMC

131

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Millions of people in the developing world are affected by diseases caused by the kinetoplastid parasites: the leishmaniases, African trypanosomiasis, and Chagas disease. In many cases the drugs employed for treatment are toxic, marginally effective, given by injection, and/or compromised by the development of resistance. Since safe, effective, and affordable chemotherapeutic agents for leishmaniasis and trypanosomiasis are clearly needed, the identification of new antikinetoplastid drug candidates should be an urgent priority. Numerous plant-derived natural products from different structural classes have been investigated as antileishmanial and antitrypanosomal candidates, including various alkaloids, terpenoids, flavonoids, and quinonoids. This review outlines the antikinetoplastid activities of plant-derived natural products reported in the literature and also provides an overview of mechanistic studies that have been conducted with these compounds. Given the activities of these agents and their diverse range of effects on parasite biology, natural products are a potentially rich source of drug candidates and leads against leishmaniasis and trypanosomiasis.

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Analysis of stereoelectronic properties of camptothecin analogues in relation to biological activity

Cited by 30 publications

References 16 publications

Minor Alkaloids FromGuatteria dumetorumwith Antileishmanial Activity

Minor Alkaloids FromGuatteria dumetorumwith Antileishmanial Activity

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

Natural Products from Plants as Drug Candidates and Lead Compounds Against Leishmaniasis and Trypanosomiasis

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