At present, screening for anticancer shikonin derivatives is based on cellular level to find compounds with stronger cytotoxicity. Though several compounds have been discovered with striking cytotoxicity in vitro, however, no selectivity was observed and undoubtedly, the further outcomes have been disappointing because of their great damage to normal cells. Meanwhile, the presumed mechanisms of action are also established in terms of their cytotoxicity. From a pharmacological point of view, most of the shikonin derivatives are at an early stage of their development, and thus it is difficult to determine the exact effectiveness in cancer treatment. With research in this field going deeper, it can be expected that, despite the difficulties, shikonin derivatives as potential anticancer agents will soon follow.

Forty-three 1,5-diheteroaryl-1,4-pentadien-3-ones were designed as potential curcumin mimics, structurally featuring a central five-carbon dienone linker and two identical nitrogen-containing aromatic rings. They were synthesized using a Horner–Wadsworth–Emmons reaction as the critical step and evaluated for their cytotoxicity and antiproliferative activities toward both androgen-insensitive and androgen-sensitive prostate cancer cell lines and an aggressive cervical cancer cell line. Most of the synthesized compounds showed distinctly better in vitro potency than curcumin in the four cancer cell lines. The structure–activity data acquired from the study validated (1E,4E)-1,5-dihereroaryl-1,4-pentadien-3-ones as an excellent scaffold for in-depth development for clinical treatment of prostate and cervical cancers. 1-Alkyl-1H-imidazol-2-yl, ortho pyridyl, 1-alkyl-1H-benzo[d]imidazole-2-yl, 4-bromo-1-methyl-1H-pyrazol-3-yl, thiazol-2-yl, and 2-methyl-4-(trifluoromethyl)thiazol-5-yl were identified as optimal heteroaromatic rings for the promising in vitro potency. (1E,4E)-1,5-Bis(2-methyl-4-(trifluoromethyl)thiazol-5-yl)penta-1,4-dien-3-one, featuring thiazole rings and trifluoromethyl groups, was established as the optimal lead compound because of its good in vitro potency and attractive in vivo pharmacokinetic profiles.

The increasing demand of electronic devices for physical motion detection has encouraged the development of highly elastic strain sensors. Especially, to capture wide-range physical movements, supremely stretchable and wide-range strain sensors are required. Here, a novel transparent, bendable, stretchable, and wide-range strain sensor based on a sandwich-like stacked graphene and Ag-nanowires hybrid structures is reported. The hybrid structures on 200% pre-stretched polyacrylate (PAC) are patterned which possess good bendability up to 2 mm radius, impressive stretchability up to 200% and comparatively low sheet resistance ≈200 Ω sq with transparency 85%. Pre-stretched PAC technique enables the sensor to work well at extremely high strains and to sense the multidirectional strains efficiently. The Ag-nanowires pattern on PAC is fabricated via the bubble-template method, by which a uniform distribution of Ag-nanowires is achieved with significant connectivity throughout the surface. This not only decreases the power consumption but also enhances the sensitivity of the strain sensor. The demonstrated strain sensor is capable to sense strains between 5% and 200%, and the response time for this sensation is <1 ms.

Illisimonin A, an unprecedented sesquiterpenoid with a tricyclo[5.2.1.0]decane skeleton, was isolated from the fruits of Illicium simonsii. The structure and absolute configuration of 1 were determined using extensive spectroscopic evidence and electronic circular dichroism (ECD) calculations. It was determined that 1 possesses a caged 2-oxatricyclo[3,3,0,1]nonane ring system fused to a five-membered carbocyclic ring and a five-membered lactone ring. A plausible biogenetic pathway for 1 was proposed, and 1 showed neuroprotective effects against oxygen-glucose deprivation (OGD)-induced cell injury in SH-SY5Y cells with an EC value of 27.72 μM.

13a-(S)-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) is a novel oral anti-glioma pro-drug with a potent anti-tumor effect against temozolomide-resistant glioma in vivo. However, poor lipid solubility has limited the encapsulation efficacy during formulation development. Moreover, although the active metabolite of CAT3, 13a(S)-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (PF403), can penetrate the blood-brain barrier and approach the brain tissue with a 1000-fold higher anti-glioma activity than CAT3 in vitro, its bioavailability and Cmax were considerably low in plasma, limiting the anti-tumor efficacy. In this study, a novel oleic acid-CAT3 conjugate (OA-CAT3) was synthesized at the first time to increase the lipid solubility of CAT3. The OA-CAT3 loaded solid lipid nanoparticles (OA-CAT3-SLN) were constructed using an ultrasonic technique to enhance the bioavailability and Cmax of PF403 in plasma. Our results demonstrated that CAT3 was amorphous in the lipid core of OA-CAT3-SLN and the in vitro release was well controlled. Furthermore, the encapsulation efficacy and the zeta potential increased to 80.65 ± 6.79% and −26.7 ± 0.46 mV, respectively, compared to the normal CAT3 loaded SLN. As indicated by the high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) quantitation, the monolayer cellular transepithelial transport rate of OA-CAT3-SLN improved by 2.42-fold relied on cholesterol compared to the CAT3 suspension. Hence, the in vitro cell viability of OA-CAT3-SLN in C6 glioma cells decreased to 29.77% ± 2.13% and 10.75% ± 3.12% at 48 and 72 h, respectively. Finally, compared to the CAT3 suspension, the in vivo pharmacokinetics in rats indicated that the plasma bioavailability and Cmax of PF403 as afforded by OA-CAT3-SLN increased by 1.7- and 5.5-fold, respectively. Overall, the results indicate that OA-CAT3-SLN could be an efficacious delivery system in the treatment of glioma.

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PurposeGlioblastoma multiforme (GBM) is a malignant high-grade glioma with a poor clinical outcome. Temozolomide (TMZ) is the first-line GBM chemotherapy; however, patients commonly develop resistance to its effects.Materials and methodsWe investigated the antitumor activity of CAT3 in TMZ-resistant glioblastoma cell lines U251/TMZ and T98G. Orthotopic and subcutaneous mice tumor models were used to investigate the effects of various treatment regimes.ResultsWe found that PF403, the active metabolite of CAT3, inhibited proliferation of both cell lines. PF403 repressed the Hedgehog signaling pathway in the U251/TMZ cell line, reduced O6-methylguanine DNA methyltransferase (MGMT) expression, and abolished the effects of the Shh pathway. Moreover, PF403 blocked the Hedgehog signaling pathway in T98G MGMT-expressing cells and downregulated the expression of MGMT. CAT3 suppressed growth in the U251/TMZ orthotopic and T98G subcutaneous xenograft tumor models in vivo. We also demonstrated that inhibition of the Hedgehog pathway by PF403 counteracted TMZ resistance and enhanced the antitumor activity of TMZ in vitro and in vivo.ConclusionThese results indicate that CAT3 is a potential therapeutic agent for TMZ-resistant GBM.