concentration of a drug that is required for 50% inhibition in vitro after 72 h of treatment with the test compounds. Five serial dilutions (from 12.5 to 100 µM) for each sample were evaluated in triplicate. The results obtained from these assays are shown in Table 1. The compounds 2-4 and 6 did not affect the viability of the cells lines studied, however the compounds 1 and 5 showed IC 50 values with inhibitory activity, ranged in the 80 µM level for breast cancer
Some aspects related to the relation between the structures and the observed cytotoxicity deserve comment. In the case of two subsets of hybrid molecules  where there are differences between in the carbon chain length (e.g. 1-4 and 5-8), the cytotoxicity reaches a maximum for compounds having a ten- carbon chain in the combretastatin A-4 segment (3, 7). The cytotoxicities of the compounds of the enantiomeric series (ent-1 to ent-4) are not too different from those of 1-4, even though the maximum cytotoxicity is found here for ent-1, the compound with the shorter carbon chain. It is difficult to propose now an explanation for this fact, as we do not yet know whether these compounds are
(17) (a) Yasui, K.; Tamura, Y.; Nakatani, K.; Kawada, K.; Ohtani, M. Total synthesisof (−)-PA-48153C, a novel immunosuppressive 2- pyranone derivative. J. Org. Chem. 1995, 60, 7567 − 7574. (b) Gurjar, M. K.; Henri, J. T., Jr.; Bose, D. S.; Rao, A. V. R. Total synthesisof a potent immunosuppressant pironetin. Tetrahedron Lett. 1996, 37, 6615−6618. (c) Chida, N.; Yoshinaga, M.; Tobe, T.; Ogawa, S. Total synthesisof (−)-PA-48153C (pironetin) utilising l-quebrachitol as a chiral building block. Chem. Commun. 1997, 1043−1044. (d) Wata- nabe, H.; Watanabe, H.; Bando, M.; Kido, M.; Kitahara, T. An efficient synthesisof pironetins employing a useful chiral building block, (1S,5S,6R)-5-hydroxybicyclo[4.1.0]heptan-2-one. Tetrahedron 1999, 55, 9755−9776. (e) Keck, G. E.; Knutson, C. E.; Wiles, S. A. Total synthesisof the immunosupressant (−)-pironetin (PA48153C). Org. Lett. 2001, 3, 707−710. (f) Dias, L. C.; de Oliveira, L. G.; de Sousa, M. A. Total synthesisof (−)-pironetin. Org. Lett. 2003, 5, 265−268. (g) Shen, X.; Wasmuth, A. S.; Zhao, J.; Zhu, C.; Nelson, S. G. Catalytic asymmetric assembly of stereodefined propionate units: an enantio- selective total synthesisof ( − )-pironetin. J. Am. Chem. Soc. 2006, 128, 7438−7439. (h) Enders, D.; Dhulut, S.; Steinbusch, D.; Herrbach, A. Asymmetric total synthesisof (−)-pironetin employing the SAMP/ RAMP hydrazone methodology. Chem.Eur. J. 2007, 13, 3942−3949. (i) Bressy, C.; Vors, J.-P.; Hillebrand, S.; Arseniyadis, S.; Cossy, J. Asymmetric total synthesisof the immunosuppressant ( − )-pironetin. Angew. Chem., Int. Ed. 2008, 47, 10137 − 10140. (j) Crimmins, M. T.; Dechert, A.-M. R. Enantioselective total synthesisof ( − )-pironetin: iterative aldol reactions of thiazolidinethiones. Org. Lett. 2009, 11, 1635−1638. (k) Yadav, J. S.; Ather, H.; Rao, N. V.; Reddy, M. S.; Prasad, A. R. Stereoselective synthesisof (−)-pironetin by an iterative Prins cyclisation and reductive cleavage strategy. Synlett 2010, 1205− 1208.
in size from one to nine isoprene units. In particular, sesquiterpene hydroquinones from sponges such as arenarol, fulvanin-2, yahazunol, avinosol and avarol offer promising opportunities for the development of new antitumor agents . Based on these premises, the potential of meroterpenes is of great interest; however, low yields of these compounds have traditionally been obtained from natural sources [5–8]. For these reasons, research efforts to chemically synthesize these compounds, their structural analogs, and their derivatives have intensified in recent decades [9–12]. However, little has been done on the synthesisand biological evaluation of hybrid molecules combining cyclic monoterpenes and synthetic phenols [13–15]. One of the best known cyclic monoterpenes is perillyl alcohol, a small lipophilic allylic alcohol found predominantly in essential oils from Perilla frutescens, cherries, cranberries, lavender, celery seed and spearmint [16,17], which exhibit chemopreventive andcytotoxicactivity against a wide variety of cancer cell lines [18–24]. Additionally, the present findings suggest that perillyl alcohol may be used as a prototype for the prevention of ethanolic liver injury and in therapy of patients with malignant brain tumors [25,26]. These facts motivated us to accomplish the synthesisof novel cyclodiprenyl phenols from perillyl alcohol 1 and different phenol moieties. In terms of application, our final aim was the evaluation of their biological activity as potential antiproliferative agents against a panel of cancer cell lines.
Chalcones bearing prenyl groups are an abundant subclass of naturally occurring chalcones . The biosynthesis of C-prenyl chalcones involves the coupling of products from the shikimic and mevalonic acid pathways. The latter produces the prenyl group, while the former produces the aromatic compound. The two products are linked together by prenyl tranferase enzymes . Almost 80% of these molecules are monoprenylated and the remaining 20% consist of di and/or triprenyl derivatives. C-prenylation takes place more frequently on ring A at positions 3 0 and/or 5 0 , as well as 3 and/or 5 . Prenylated chalcones have been isolated from plants mainly belonging to the families of Leguminosae and Moraceae . This class of compounds has been found to display a variety of biological activities that are anticarcinogenic, antiprotozoal, larvicidal, anti-inflammatory, antibacterial, antioxidant, and antifungal [5,6]. A representative example of naturally occurring bioactive C-prenylated chalcones, isocordoin (1), was isolated from Lonchocarpus species [7,8] or Aeschynomene fascicularis . Isocordoin has been found to have a range of interesting biological properties in vitro that may have therapeutic and industrial
The extracts considered as active were processed by fractionation and isolation of the major substances. The extract of dichloromethane (PPD) of the species of P. piedecuestanum Trel. and Yunck. (4.89 g) was active and was fractionated by column chromatography using as eluent gradients of petroleum ether: ethyl acetate, EtOAc and MeOH. Thirty fractions were obtained from which fraction 10 was taken and column chromatography was performed using petroleum ether, petroleum ether: DCM (1: 1), DCM, gradients of DCM: EtOAc and finally MeOH as eluent. Twenty three fractions were obtained which were pooled between 1-7 and preparative plate chromatography was performed using DCM as the eluent and 20 mg of the compound designated as (4) were purified. On the other hand, to section 25 of the dichloromethane extract column, preparative layer chromatography was performed and two compounds were isolated, one of which was a yellow amorphous solid named (2) (31.8 mg) and the other a crystalline orange solid referred to as (1) (183.9 mg). The remaining fractions of the petroleum ether extract and dichloromethane were combined to perform column chromatography again using petroleum ether gradients: DCM, DCM: EtOAc, EtOAc: Methanol (MeOH) gradients and finally MeOH and obtained 14 fractions, fractions of 6-10 were taken and column chromatography using eluent petroleum ether, petroleum ether: DCM (1: 1), DCM and DCM: MeOH gradients as eluents, whereby 30 fractions, fractions 1-9 and 15-17 were taken for preparative plate chromatography eluting with petroleum ether: DCM 25: 3 and DCM to isolate 39 mg of the compound (4), 59 mg of compound (3) and 58 mg of compound (5). Halogenated atoms were introduced into the isolated compounds by the production of brominated derivatives. Only a successful reaction was performed from compound (5). The experimental procedure is briefly described below: a solution of (5) (20 mg, 0.71 mmol) was dissolved in N, N-Dimethylformamide (DMF) and N-Bromosuccinimide NBS
Quinones are compounds widely found in nature that possess well-known biological properties. Therefore, their study repre- sents a privileged interest for the pharmaceutical industry (Martı´nez and Benito 2005; Salas et al., 2011; Kumagai et al., 2012; Tandon and Kumar 2013; Klotz et al., 2014; Naujorks et al., 2015). In this sense, the most significant and largely distributed family of quinones are those based on the 1,4-naphthoquinone, which has shown a remarkable variety of therapeutic activities, antibacterial (Tandon et al., 2006; Ibis et al. 2011), antiviral (Tandon et al., 2006), antifungal (Tandon et al. 2009; Ferreira Mdo et al. 2014), anti-T Cruzi (Cuellar et al. 2003; Vazquez et al. 2015) and anticancer prop- erties (Mallavadhani et al., 2014; Hong et al., 2015; Wellington 2015). The activity exhibited by 1,4-naphthoquinone deriva- tives makes them very attractive as building blocks to guide the synthesisof new, promising anticancer drugs. Additionally, several action mechanisms have been postulated, including their interaction with topoisomerases, their ability to generate semiquinone radical anions and reactive oxygen species (ROS) as well as their intercalation in DNA (Asche 2005; Smith et al., 2014; Hong et al. 2015; Wellington 2015). Among the group of naphthoquinones with known antitumor activity, the fragment 2-aminonaphthoquinone stands out. This compound is included in naturally occurring compounds such as griffithaz- anone A and calothrixin A/B as well synthetic analogues, such as 2-piperazinyl-naphthoquinone (Fig. 1) (Chen et al., 2003; Zhou et al., 2009; Tip-pyang et al., 2010).
SUMMARY. The development of novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) offers the possibility of generating novel structures of increased potency. Based on the bioisosterism principle, two novel 2-(5-(naphthalen-1-yl)-1,2,3-thiadiazol-4-ylthio)-N-acetamides derivatives have been designed, synthe- sized and evaluated for their anti-HIV activities in MT-4 cells. The results indicate that these compounds show good activities against HIV-1. Especially, compound 9B (EC
The investigation has shown that the most effective coordination compounds used as anticancer medicines, based on DNA binding, are cisplatin, oxaliplatin, carboplatin and nedaplatin, which are metalocomplexes platinum (II) x . These medications revolutionized chemotherapy as from the late seventies to be active against resistant tumors commercial drugs. Despite its high activity, the application of cisplatin and similar compounds has significant disadvantages which include: poor water solubility, severe side effects that are typical of the heavy metal toxicity, and the development of drug tolerance from the tumor. The last two are the main driving force behind the current research in the field of development of new anticancer agents.
No significant effect on cell viability for the uridine andderivatives was observed with p<0.05, these substances did not present a dose-response relationship. However, the compound 3’,4’-uridine acetonide, showed a differential ef- fect and a higher activity over cell viability on MCF-7 hu- man cancer breast cell line than for the CHO-K1 cell line. Breast cancer cell line MCF-7 employed, according to re- sults, possibly presented resistance to uridine nucleoside. Some of the uridine derivatives, particularly with fatty ac- ids are too bulky, this property can inhibit the hydrolysis of 6’-acyl-ester gruop of the ribose and produce decreassed of phosphorylation (activation) of the nucleoside.
control. Moreover, dunnione was used as a positive control although this compound did not show structural similarity with the analysed compounds. After 72 h exposure, in vitro cytotoxicity was measured by the SRB dye assay. Cells were fixed by adding cold 50% (wt/vol) trichloroacetic acid (TCA, 25 µL) and incubating for 60 min at 4 ºC. Plates were washed with deionized water and dried; SRB solution (0.1% wt/vol in 1% acetic acid, 50 µL) was added to each microtiter well and incubated for 30 min at room temperature. Unbound SRB was removed by washing with 1% acetic acid. Plates were air-dried and bound stain was solubilized with Tris base (100 µL, 10 mM). Optical densities were read on an automated spectrophotometer plate reader at a single wavelength of 540 nm. Values shown are % viability vs. Ctrl + SD, n = four independent experiments in triplicate. CONCLUSIONS
The COSY H-H spectrum for 3’,4’,6’-O-acetyl-uridine in DMSO-d6 presents at high-field, a multiplet coupling with shift δ=4.25 ppm equivalent to three protons (correspond- ing to overlapping of H-5’ and H-6’ protons of ribose ring) with a high deshielding signal δ=5.44 ppm (H-3’). Further- more, this proton presents two couplings, with a shielding signal localized at δ=5.33 (H-4’) and other highly deshield- ed signal δ=5.87 ppm corresponding to an anomeric pro- ton (H-2’) of the ribose ring. At down-field, a coupling be- tween the proton appeared at δ=5.72 ppm (H-5 uracil ring) with the highest deshielding δ=7.69 (H-6 uracil ring). The COSY H-H spectrum for the 4-N-acetyl-3’,4’,6’-O-triacetyl- cytarabine in CDCl 3 shows at high field that the signals for the H-5’ and H-6’protons of arabinofuranosyl ring are not overlapped, neither are the H-3’and H-4’ protons. How- ever, it is possible to observe a coupling between protons with higher shielding δ=4.16 ppm (H-5’) of arabinofura- nosyl ring and the signals at δ=4.33 ppm (H-6’). Moreover, an intense coupling is observed for the proton localized at δ=5.49 ppm (H-3’) with a high deshielding signal, δ=6.29 ppm corresponding to an anomeric proton (H-2’) of the ribose ring. At down-field, it is observed a coupling be- tween two deshielding signals, localized at δ=7.43 ppm and δ=7.88, corresponding to H-5 and H-6 protons of cytosine ring, respectively.
From a theoretical point of view, leptocarpin under acid conditions can produce two types of cyclation products. First, an eudesmanolide type lactone by attack of the double bond ∆ 4,5 on C10 (6-Exo-Tet) producing the opening of the oxirane ring (Figure 3). The second product could be a guaianolide type lactone produced by the binding of carbons C5-C1 (5-Exo-Tet) as a consequence of the double bond ∆ 4,5 attack on C1 36 . Nevertheless, this did not happen and a
TBMs may be divided in two broad categories, those that bind to a -tubulin and those that bind to b -tubulin. The latter group is presently by far the most numerous and contains products which cause either disruption or stabilization of microtubules. Among the drugs that belong to this group, the well-known colchicine  and the combretastatins  (Fig. 1) exert their effects by causing disruption of microtubules. In contrast, another important repre- sentative of the same group, paclitaxel, was the ﬁ rst-described tubulin-binding drug that was found to stabilize microtubules . Even though they display opposite effects, these drugs are known to bind to b -tubulin, whenever to different sites within this protein subunit [9 e 11].