- Synthesis and Evaluation of New Naphthalene and Naphthoquinone Derivatives as Anticancer Agents
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DNA topoisomerase I inhibitors, both synthetic and of natural origin, are receiving increasing consideration primarily as drugs against refractory tumors. Alkannin and shikonin, two enantiomeric dyes from Alkanna tinctoria and Lithospermum erythrorhizon, have been known over many centuries as dyestuff, wound healing, anti-inflammatory, antibacterial and antitumor substances. Although multiple mechanisms appear to be implicated, their potency is associated with the inhibition of topoisomerase I and with the redox properties of the naphthazarin scaffold. Here, the synthesis of new naphthalene and naphthoquinone derivatives inspired by alkannin and shikonin is described and their structural and biological properties were examined. Different oxidation states of the naphthalene nucleus were examined to observe the effect of this parameter on cytotoxicity. Antiproliferative activities against a panel of human cancer cell lines were evaluated and the implication of topoisomerase I was assessed.
- Beretta, Giovanni L.,Ribaudo, Giovanni,Menegazzo, Ileana,Supino, Rosanna,Capranico, Giovanni,Zunino, Franco,Zagotto, Giuseppe
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- Asymmetric synthesis of alkannin and shikonin
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A new general and convergent route for the synthesis of the title compounds is presented. The polyoxygenated aromatic ring system is annulated in one operation by the condensation of a Michael type acceptor with an 1,4 dipole equivalent. The chiral center of the target is introduced via an asymmetric allyl boration in high ee. Overall, the fully protected natural product is constructed within 8 steps in 35% total yield.
- Couladouros, Elias A.,Plyta, Zoi F.,Strongilos, Alexandros T.,Papageorgiou, Vassilios P.
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- Discovery of heterocycle-containing α-naphthoflavone derivatives as water-soluble, highly potent and selective CYP1B1 inhibitors
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Cytochrome P450 1B1 (CYP1B1) has been well validated as an attractive target for cancer prevention and drug resistance reversal. In continuation of our interest in this area, herein, a set of forty-six 6,7,10-trimethoxy-α-naphthoflavone derivatives varying in B ring was synthesized and screened against CYP1 enzymes, leading to the identification of fluorine-containing compound 15i as the most potent and selective CYP1B1 inhibitor (IC50 value of 0.07 nM), being 84-fold more potent than that of the template molecule ANF. Alternatively, the amino-substituted derivative 13h not only possessed a potent inhibitory effect on CYP1B1 (IC50 value of 0.98 nM), but also had a substantially increased water solubility as compared with the lead ANF (311 μg/mL for 13h and 5 μg/mL for ANF). The current study expanded the structural diversity of CYP1B1 inhibitors, and compound 13h could be considered as a promising starting point with great potential for further studies.
- Dong, Jinyun,Huang, Guang,Cui, Qing,Meng, Qingqing,Li, Shaoshun,Cui, Jiahua
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- Development of benzochalcone derivatives as selective CYP1B1 inhibitors and anticancer agents
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A series of benzochalcone derivatives have been synthesized and evaluated for CYP1 inhibitory activity and cytotoxic properties against wild type cell lines (MCF-7 and MDA-MB-231) and drug resistant cell lines (LCC6/P-gp and MCF-7/1B1). All of these compounds were found to have selective inhibition towards CYP1B1 and the most potent two possessed single-digit nanomolar CYP1B1 potency. In addition, some of them showed promising cytotoxic activities not only against wild type cells, but also against drug resistant cells at low micromolar concentrations. More importantly, these multi-functional compounds may surmount drug-drug interactions that frequently occur during the combination of CYP1B1/P-gp inhibitors and anticancer drugs to overcome drug resistance. This study may provide a good starting point for the further development of more potent multi-functional agents with CYP1B1 inhibitory activity and cytotoxic potency in cancer prevention and treatment.
- Dong, Jinyun,Huang, Guang,Zhang, Qijing,Wang, Zengtao,Cui, Jiahua,Wu, Yan,Meng, Qingqing,Li, Shaoshun
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p. 1606 - 1614
(2019/09/30)
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- 6-Substituted 1,4-Naphthoquinone Oxime Derivatives (III): Synthesis and Cytotoxic Evaluation
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As a continuous study, a set of 23 new 6-substituted 1,4-naphthoquinone oxime derivatives are synthesized and screened for their in vitro cytotoxic activity. Four of those oxime derivatives demonstrate more potent cytotoxic activity towards K562, HCT-15, and HCT-116 cell lines than a reference drug 5-Fu. In particular, compound 21g exhibits the strongest inhibitory activity against K562 cell lines with IC50 values of 1.25 μM. According to flow cytometry data, compound 21g can arrest cell cycle at S phase and induce a strong apoptotic response in K562 cells. The preliminary structure-activity relationship study shows that the nature of substituents in positions 6 and 1' of 1,4-naphthoquinone derivatives significantly affect their cytotoxic activity.
- Huang,Liu,Meng,Li
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p. 1025 - 1035
(2018/07/06)
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- An efficient reduction of nitro and bromine naphthalene derivatives
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Reduction of 1,5-dimethoxy-4-nitronaphthalene by hydrazine hydrate was optimized in the course of current study. Influence of metals, temperature and solvents upon the process was tested. Yield of the reaction was the highest in the presence of Zn powder in DMF. Moderate heating made the process slightly more efficient than that at room temperature, whereas high temperature led to a decreased yield. The current approach made it possible to exclude high pressure and diminish experimental costs.
- Dong,Zhang,Huang,Meng,Li
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p. 837 - 841
(2017/05/29)
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- Synthesis, antibacterial and antifungal activities of naphthoquinone derivatives: a structure–activity relationship study
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The synthesis of 1,4-naphthoquinone derivatives is of great interest since these compounds exhibit strong activity as antimalarial, antibacterial, antifungal and anticancer agents. A series of 50 naphthoquinone derivatives was synthesized and evaluated for antibacterial and antifungal activity against Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, Candida krusei, Candida parapsilosis and Cryptococcus neoformans using the broth microdilution method. The Candida species were the most susceptible microorganisms. Halogen derivatives of 1,4-naphthoquinone presented strong activity, e.g., 2-bromo-5-hydroxy-1,4-naphthoquinone, which exhibited inhibition at an MIC of 16?μg/mL in S. aureus, and 2-chloro-5,8-dihydroxy-1,4-naphthoquinone, with an MIC of 2?μg/mL in C. krusei. These compounds showed higher activity against fungi, but the antibacterial activities were very low. The study of structure–activity relationships is very important in the search for new antimicrobial drugs due to the limited therapeutic arsenal.
- Sánchez-Calvo, Juan M.,Barbero, Gara R.,Guerrero-Vásquez, Guillermo,Durán, Alexandra G.,Macías, Mariola,Rodríguez-Iglesias, Manuel A.,Molinillo, José M. G.,Macías, Francisco A.
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p. 1274 - 1285
(2016/07/06)
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- Practical first total synthesis of the potent phytotoxic (±)-naphthotectone, isolated from tectona grandis
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Naphthotectone is a quinone isolated recently from teak extracts of Tectona grandis. It has been shown to be one of the most abundant compounds and the most active compound isolated form teak. Thus, it has been proposed that naphthotectone is one of the compounds responsible for the allelophathic activity of this plant. An efficient total synthesis of (±)- naphthotectone was achieved in seven steps and 31 % overall yield. The best results were obtained by using an aqueous Wittig reaction as a key step. Other reactions used were the formation of an epoxide ring by the Corey-Chaykovsky method, and an innovative one-pot anodic electrooxidation and demethylation. An efficient total synthesis of (±)-naphthotectone was achieved in seven steps and 31 % overall yield. This natural product has been proposed as one of the compounds responsible for the allelopathic activity of Tectona grandis. The synthetic route includes an aqueous Wittig olefination, a Corey-Chaikovsky epoxidation, and an innovative one-pot anodic electrooxidation and demethylation.
- Guerrero-Vasquez, Guillermo A.,Andrade, Carlos Kleber Z.,Molinillo, Jose M. G.,MacIas, Francisco A.
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p. 6175 - 6180
(2013/09/24)
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- An efficient synthesis of 2-formyM,4,5,8-tetramethoxynaphthalene
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An improved synthetic method of 2-formyl-1,4,5,8-tetramethoxynaphthalene in 73% overall yield is described. This method has several advantages compared with the reported synthesis: first, the reactant is cheaper and the yield is higher; second, the reaction condition is milder and the reagent used is more friendly to environment; third, the work-up of each step is simpler; fourth, the protocol reported is more suitable for large-scale preparation.
- Wang, Rubing,Zheng, Xiaogang,Zhou, Wen,Peng, Ying,Zhu, Mengyuan,Li, Shaoshun
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experimental part
p. 520 - 521
(2010/12/25)
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- A convenient synthesis of 2-formyl-1,4,5,8-tetramethoxynaphthalene
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A convenient and concise synthesis of 1,4,5,8-tetramethoxynaphthalene can be achieved by methylation of 2,3-dihydronaphthazarin with dimethylsulfate in the presence of phase transfer catalytic in 90.3% yield, then formylation of 1,4,5,8-tetramethoxynaphthalene can afford 2-formyl-1,4,5,8- tetramethoxynaphthalene in 96.2% yield.
- Xu, De-Feng,Guan, Peng-Jian,Li, Shao-Shun
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p. 779 - 780
(2007/10/03)
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- A new efficient route for multigram asymmetric synthesis of alkannin and shikonin
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A short and convergent approach for the synthesis of alkannin, shikonin and shikalkin is presented. A Hauser-type annulation of cyanophthalide 26 with enone 7 affords the complete aromatic system in just one step with concomitant attachment of the entire side chain. Subsequent Corey's oxazaborolidine mediated asymmetric reduction of the above advanced intermediate, leads to the required isomer in high enantiomeric excess. Finally, a selective and high yielding deprotection protocol furnishes the title compounds as pure crystalline precipitates. Thus, a multigram synthesis of shikonin, alkannin and shikalkin is achieved in high yield and enantioselectivity.
- Couladouros, Elias A.,Strongilos, Alexandros T.,Papageorgiou, Vassilios P.,Plyta, Zoi F.
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p. 1795 - 1803
(2007/10/03)
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- Total Synthesis of Shikalkin
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The first total syntheses of dihydroshikalkin and shikalkin were accomplished.
- Terada, Akira,Tanoue, Yasuhiro,Hatada, Akira,Sakamoto, Hiroshi
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p. 987 - 988
(2007/10/02)
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