Multivariate SAR and QSAR of cucurbitacin derivatives as cytotoxic compounds in a human lung adenocarcinoma cell line

Lang, Karen L.; Silva, Izabella Thaís; Machado, Vanessa Rocha; Zimmermann, Lizandra M.; Miguel, S. B.; Simões, Cláudia Maria Oliveira; Schenkel, Eloir Paulo; Durán, Fernando Javier; Bernardes, Lílian Sibelle Campos; Melo, Eduardo Borges de

doi:10.1016/j.jmgm.2013.12.004

Cited by 14 publications

(8 citation statements)

References 71 publications

(113 reference statements)

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“…In this molecule, there are two important features to consider: the double bond between C1 and C2 with the polar group attached in position 2 (in this case nitrogen), and the Michael acceptor in the side chain. These functionalities have been validated as pharmacophores in our previous QSAR work [ 40 ]. Changing the hydroxyl group by the amino moiety in C2, DACE has a nucleophilic, basic and hydrogen bond donor/acceptor group instead of a donor/acceptor group.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Antitumor Activity of a Novel Semisynthetic Derivative of Cucurbitacin B

et al. 2015

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Lung cancer is the most deadly type of cancer in humans, with non-small-cell lung cancer (NSCLC) being the most frequent and aggressive type of lung cancer showing high resistance to radiation and chemotherapy. Despite the outstanding progress made in anti-tumor therapy, discovering effective anti-tumor drugs is still a challenging task. Here we describe a new semisynthetic derivative of cucurbitacin B (DACE) as a potent inhibitor of NSCLC cell proliferation. DACE arrested the cell cycle of lung epithelial cells at the G2/M phase and induced cell apoptosis by interfering with EGFR activation and its downstream signaling, including AKT, ERK, and STAT3. Consistent with our in vitro studies, intraperitoneal application of DACE significantly suppressed the growth of mouse NSCLC that arises from type II alveolar pneumocytes due to constitutive expression of a human oncogenic c-RAF kinase (c-RAF-1-BxB) transgene in these cells. Taken together, these findings suggest that DACE is a promising lead compound for the development of an anti-lung-cancer drug.

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Antitumor Activity of a Novel Semisynthetic Derivative of Cucurbitacin B

et al. 2015

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“…인체와 환경독성의 유발은 단일물질보다 혼합물질 노출에 의한 영향이 크지만 (Yang et al, 1998 (Aruoja et al, 2014;Kar & Roy, 2014;Lang et al, 2014 (Rathbun, 1990;Melcer, 1994…”

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Changes in Physico-chemical Properties of Single or Mixture State of DMF, MEK and Toluene in Synthetic Leather Factories

Kim¹,

Won²,

Park³

et al. 2014

Journal of Korean Society of Occupational and Environmental Hyg

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Objectives: It was known that workers in synthetic leather company are mainly co-exposed to dimethylformamide(DMF) with methyl ethyl ketone(MEK) or toluene(TOL) instead of a single dimethylformamide. This study was examined to the physico-chemical properties in single DMF and binary mixture DMF with MEK or TOL. Materials: Physico-chemical properties were measured by Korean and American Standard Test Methods. Results: Boiling point, specific gravity and flash point in single DMF were significantly higher than binary mixture DMF with MEK or TOL and such difference was dependent on the mixing ratio of MEK and TOL, and low explosion limit in binary mixture DMF with TOL was only significantly lower than single DMF. However, Reid vapor pressure had significantly higher in binary mixture DMF with MEK or TOL compared with single DMF. Conclusions: Our results demonstrate that the binary mixture DMF with MEK or TOL synergistically increases volatilization of DMF. It was concluded that the interaction between DMF and MEK and/or TOL might play a key role in the volatilization process of DMF under environmental conditions of workplace.

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“…In the sequence, the Ordered Predictors Selection (OPS) variable selection method, available in the QSAR Modeling program, was used [27, 28]. After the variable selection, which also uses the PLS regression method, the model was constructed and refined using the PLS-DA [29, 30]. The aim of this last stage was to maximize the capacity of classification of the model.…”

Section: Methodsmentioning

confidence: 99%

Novel coumarins active against Trypanosoma cruzi and toxicity assessment using the animal model Caenorhabditis elegans

Soares

Göethel

Kagami

et al. 2019

BMC Pharmacol Toxicol

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BackgroundChagas disease (CD) is a tropical parasitic disease. Although the number of people infected is very high, the only drugs available to treat CD, nifurtimox (Nfx) and benznidazole, are highly toxic, particularly in the chronic stage of the disease. Coumarins are a large class of compounds that display a wide range of interesting biological properties, such as antiparasitic. Hence, the aim of this work is to find a good antitrypanosomal drug with less toxicity. The use of simple organism models has become increasingly attractive for planning and simplifying efficient drug discovery. Within these models, Caenorhabditis elegans has emerged as a convenient and versatile tool with significant advantages for the toxicological potential identification for new compounds.MethodsTrypanocidal activity:Forty-two 4-methylamino-coumarins were assayed against the epimastigote form of Trypanosoma cruzi (Tulahuen 2 strain) by inhibitory concentration 50% (IC50).Toxicity assays:Lethal dose 50% (LD50) and Body Area were determined by Caenorhabditis elegans N2 strain (wild type) after acute exposure.Structure-activity relationship:A classificatory model was built using 3D descriptors.ResultsTwo of these coumarins demonstrated near equipotency to Nifurtimox (IC50 = 5.0 ± 1 μM), with values of: 11 h (LaSOM 266), (IC50 = 6.4 ± 1 μM) and 11 g (LaSOM 231), (IC50 = 8.2 ± 2.3 μM). In C. elegans it was possible to observe that Nfx showed greater toxicity in both the LD50 assay and the evaluation of the development of worms. It is possible to observe that the efficacy between Nfx and the synthesized compounds (11 h and 11 g) are similar. On the other hand, the toxicity of Nfx is approximately three times higher than that of the compounds. Results from the QSAR-3D study indicate that the volume and hydrophobicity of the substituents have a significant impact on the trypanocidal activities for derivatives that cause more than 50% of inhibition. These results show that the C. elegans model is efficient for screening potentially toxic compounds.ConclusionTwo coumarins (11 h and 11 g) showed activity against T. cruzi epimastigote similar to Nifurtimox, however with lower toxicity in both LD50 and development of C. elegans assays. These two compounds may be a feasible starting point for the development of new trypanocidal drugs.

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Multivariate SAR and QSAR of cucurbitacin derivatives as cytotoxic compounds in a human lung adenocarcinoma cell line

Cited by 14 publications

References 71 publications

In Vitro and In Vivo Antitumor Activity of a Novel Semisynthetic Derivative of Cucurbitacin B

In Vitro and In Vivo Antitumor Activity of a Novel Semisynthetic Derivative of Cucurbitacin B

Changes in Physico-chemical Properties of Single or Mixture State of DMF, MEK and Toluene in Synthetic Leather Factories

Novel coumarins active against Trypanosoma cruzi and toxicity assessment using the animal model Caenorhabditis elegans

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