Cytotoxic Activity, Topoisomerase I Inhibition and In Silico Studies of New Sesquiterpene-aryl Ester Derivatives of (-) Drimenol.

In this study, we aimed to evaluate two sets of sesquiterpene-aryl derivatives linked by an ester bond, their cytotoxic activities, and their capacity to activate caspases 3/7 and inhibit human topoisomerase I (TOP1). A total of 13 compounds were synthesized from the natural sesquiterpene (-)-drimenol and their cytotoxic activity was evaluated in vitro against three cancer cell lines: PC-3 (prostate cancer), HT-29 (colon cancer), MCF-7 (breast cancer), and an immortalized non-tumoral cell line (MCF-10). From the results, it was observed that 6a was the most promising compound due to its cytotoxic effect on three cancer cell lines and its selectivity, 6a was 100-fold more selective than 5-FU in MCF-7 and 20-fold in PC-3. It was observed that 6a also induced apoptosis by caspases 3/7 activity using a Capsase-Glo-3/7 assay kit and inhibited TOP1. A possible binding mode of 6a in a complex with TOP1-DNA was proposed by docking and molecular dynamics studies. In addition, 6a was predicted to have a good pharmacokinetic profile for oral administration. Therefore, through this study, it was demonstrated that the drimane scaffold should be considered in the search of new antitumoral agents.

New Brassinosteroid Analogs with 23,24-Dinorcholan Side Chain, and Benzoate Function at C-22: Synthesis, Assessment of Bioactivity on Plant Growth, and Molecular Docking Study.

The synthesis and biological evaluation of brassinosteroids (BRs) analogs with chemical modification in the side alkyl chain is a matter of current interest. Recently, a series of BR analogs with phenyl or benzoate groups in the alkyl chain have been reported. The effect of substitution in the aromatic ring on the biological activities of these new analogs has been evaluated, and the results suggest that the bioactivity is enhanced by substitution with an F atom. In this context, we have synthesized, characterized, and evaluated a series of new analogs of 23,24-bisnorcholenic type in which the benzoate group at the C-22 position is substituted with an F atom at "ortho or para" positions. Plant growth-promoting activities were evaluated by using the rice lamina inclination test and bean second internode biotest. The results obtained with both bioassays indicate that the compound with an F atom in the para position on the aromatic ring is the most active BR analog and in some cases is even more active than brassinolide. The docking study confirmed that compounds with an F atom adopt an orientation similar to that predicted for brassinolide, and the F atom in the "para" position generates an extra hydrogen bond in the predicted binding position.

New Amino Naphthoquinone Derivatives as Anti-Trypanosoma cruzi Agents Targeting Trypanothione Reductase.

To develop novel chemotherapeutic alternatives for the treatment of Chagas disease, in this study, a set of new amino naphthoquinone derivatives were synthesised and evaluated in vitro on the epimastigote and trypomastigote forms of Trypanosoma cruzi strains (NINOA and INC-5) and on J774 murine macrophages. The design of the new naphthoquinone derivatives considered the incorporation of nitrogenous fragments with different substitution patterns present in compounds with activity on T. cruzi, and, thus, 19 compounds were synthesised in a simple manner. Compounds 2e and 7j showed the lowest IC50 values (0.43 µM against both strains for 2e and 0.19 µM and 0.92 µM for 7j). Likewise, 7j was more potent than the reference drug, benznidazole, and was more selective on epimastigotes. To postulate a possible mechanism of action, molecular docking studies were performed on T. cruzi trypanothione reductase (TcTR), specifically at a site in the dimer interface, which is a binding site for this type of naphthoquinone. Interestingly, 7j was one of the compounds that showed the best interaction profile on the enzyme; therefore, 7j was evaluated on TR, which behaved as a non-competitive inhibitor. Finally, 7j was predicted to have a good pharmacokinetic profile for oral administration. Thus, the naphthoquinone nucleus should be considered in the search for new trypanocidal agents based on our hit 7j.

QSAR-driven synthesis of antiproliferative chalcones against SH-SY5Y cancer cells: Design, biological evaluation, and redesign.

Neuroblastoma is one of the most frequent types of cancer found in infants, and traditional chemotherapy has limited efficacy against this pathology. Thus, the development of new compounds with higher activity and selectivity than traditional drugs is a current challenge in medicinal chemistry research. In this study, we report the synthesis of 21 chalcones with antiproliferative activity and selectivity against the neuroblastoma cell line SH-SY5Y. Then, we developed three-dimensional quantitative structure-activity relationship models (comparative molecular field analysis and comparative molecular similarity index analysis) with high-quality statistical values (q2 > 0.7; r2 > 0.8; r2 pred > 0.7), using IC50 and selectivity index (SI) data as dependent variables. With the information derived from these theoretical models, we designed and synthesized 16 new molecules to prove their consistency, finding good antiproliferative activity against SH-SY5Y cells on these derivatives, with three of them showing higher SI than the referential drugs 5-fluorouracil and cisplatin, displaying also a proapoptotic effect comparable to these drugs, as proven by measuring their effects on executor caspases 3/7 activity induction, Bcl-2/Bax messenger RNA levels alteration, and DNA fragmentation promotion.

Chemical Analysis and In Vitro Bioactivity of Essential Oil of Laurelia sempervirens and Safrole Derivatives against Oomycete Fish Pathogens.

In this study, the essential oil (EO) from Laurelia sempervirens was analyzed by GC/MS and safrole (1) was identified as the major metabolite 1, was subjected to direct reactions on the oxygenated groups in the aromatic ring and in the side chain, and eight compounds (4 to 12) were obtained by the process. EO and compounds 4-12 were subjected to biological assays on 24 strains of the genus Saprolegnia, specifically of the species 12 S. parasitica and 12 S. australis. EO showed a significant effect against Saprolegnia strains. Compound 6 presents the highest activity against two resistant strains, with minimum inhibitory concentration (MIC) and minimum oomyceticidal concentration (MOC) values of 25 to 100 and 75 to 125 µg/mL, respectively. The results show that compound 6 exhibited superior activities compared to the commercial controls bronopol and azoxystrobin used to combat these pathogens.

(-)-Shikimic Acid as a Chiral Building Block for the Synthesis of New Cytotoxic 6-Aza-Analogues of Angucyclinones.

We describe the syntheses of nine new angucyclinone 6-aza-analogues, achieved through a hetero Diels-Alder reaction between the shikimic acid derivative-azadiene 13, with different naphthoquinones. The cytotoxic activity of the new synthesized compounds and five angucyclinones, previously reported, was evaluated in vitro against three cancer cell lines: PC-3 (prostate cancer), HT-29 (colon cancer), MCF-7 (breast cancer), and one non-tumoral cell line, human colon epithelial cells (CCD841 CoN). Our results showed that most 6-azadiene derivatives exhibited significant cytotoxic activities, which was demonstrated by their IC50 values (less than 10 µM), especially for the most sensitive cells, PC-3 and HT-29. From a chemical point of view, depending on the protected group of ring A and the pattern of substitution on ring D, cytotoxicity elicited these compounds, in terms of their potency and selectivity. Therefore, according to these chemical features, the most promising agents for every cancer cell line were 7a, 17, and 19c for PC-3 cells; 7a, 17, and 20 for HT-29 cells, and 19a for MCF-7 cells.

Antifeedant effect of polygodial and drimenol derivatives against Spodoptera frugiperda and Epilachna paenulata and quantitative structure-activity analysis.

BACKGROUND: The antifeedant activity of 18 sesquiterpenoids of the drimane family (polygodial, drimenol and derivatives) was investigated. RESULTS: Polygodial, drimanic and nordrimanic derivatives were found to exert antifeedant effects against two insect species, Spodoptera frugiperda and Epilachna paenulata, which are pests of agronomic interest, indicating that they have potential as biopesticide agents. Among the 18 compounds tested, the epoxynordrimane compound (11) and isonordrimenone (4) showed the highest activity [50% effective concentration (EC50 ) = 23.28 and 25.63 nmol cm-2 , respectively, against S. frugiperda, and 50.50 and 59.00 nmol/cm2 , respectively, against E. paenulata]. CONCLUSION: The results suggest that drimanic compounds have potential as new agents against S. frugiperda and E. paenulata. A quantitative structure-activity relationship (QSAR) analysis of the whole series, supported by electronic studies, suggested that drimanic compounds have structural features necessary for increasing antifeedant activity, namely a C-9 carbonyl group and an epoxide at C-8 and C-9. © 2018 Society of Chemical Industry.

2-Phenylaminonaphthoquinones and related compounds: synthesis, trypanocidal and cytotoxic activities.

A series of new 2-aminonaphthoquinones and related compounds were synthesized and evaluated in vitro as trypanocidal and cytotoxic agents. Some tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity and selectivity as compared with current trypanocidal drug, nifurtimox. Compound 4l exhibit higher selectivity than nifurtimox against Trypanosoma cruzi in comparison with Vero cells. Some of the synthesized quinones were tested against cancer cells and normal fibroblasts, showing that certain chemical modifications on the naphthoquinone moiety induce and excellent increase the selectivity index of the cytotoxicity (4g and 10). The results presented here show that the anti-T. cruzi activity of 2-aminonaphthoquinones derivatives can be improved by the replacement of the benzene ring by a pyridine moiety. Interestingly, the presence of a chlorine atom at C-3 and a highly lipophilic alkyl group or aromatic ring are newly observed elements that should lead to the discovery of more selective cytotoxic and trypanocidal compounds.

A new reaction: lead(IV) acetate-mediated oxidative fragmentation of homoallylic alcohols.

Treatment of a homoallylic alcohol with lead(IV) acetate in refluxing benzene for 2 hours results in an oxidative cleavage to give a carbonyl compound and an allylic acetate with high yield.

Synthesis and in vitro trypanocide activity of several polycyclic drimane-quinone derivatives.

The Diels-Alder reaction between two polygodial-derived dienes and simple quinones to yield substituted naphtho- and anthraquinones, is described. The in vitro trypanocide activity for the series was determined. Two of the new compounds showed an activity ten and two times higher, respectively, than nifurtimox and benznidazole, the medicines of choice for the treatment of the acute Chagas' disease.