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Abstract: Selective imaging and inducing mitochondrial dysfunction in tumor cells using mitochondria‐targeting probes has become as a promising approach for cancer diagnosis and therapy. Here, we report the design of a fluorescent berberine analog, dehydroberberine (DH‐BBR), as a new mitochondria‐targeting probe capable of self‐assembling into monodisperse organic nanoparticles (DTNPs) upon integration with a lipophilic counter anion, allowing for enhanced fluorescence imaging and treatment of tumors in living mice. X‐ray crystallography revealed that the self‐assembly process was attributed to a synergy of different molecular interactions, including π–π stacking, O⋅⋅⋅π interaction and electrostatic interaction between DH‐BBR and counter anions. We demonstrated that DTNPs could efficiently enter tumor tissue following intravenous injection and enhance mitochondrial delivery of DH‐BBR via an electrostatic interaction driven anion exchange process. Selective accumulation in the mitochondria capable of emitting strong fluorescence and causing mitochondrial dysfunction was achieved, enabling efficient inhibition of tumor growth in living mice. This study demonstrates promise for applying lipophilic anions to control molecular self‐assembly and tune antitumor activity of mitochondria‐targeting probes, which can facilitate to improve cancer treatment in vivo. [ABSTRACT FROM AUTHOR]

To discover more derivatives with better glucose-lowering efficacy compared with berberine, twenty-three novel compounds with 4,7,12,12a-tetrahydro-5 H -thieno[3′,2′:3,4]pyrido[1,2- b ]isoquinoline or 5,8,12,12a-tetrahydro-6 H -thieno[2′,3′:4,5]pyrido[2,1- a ]isoquinoline cores were designed, synthesized, and biologically evaluated in vitro in continuation of our previous work on indirect activators of adenosine 5′-monophosphate-activated protein kinase (AMPK). Nine compounds effectively stimulated glucose consumption (>2.3-fold at 10 μM) in L6 myotube cells, and two compounds ( 4d and 4s ) exhibited superior inhibitory activity (<57.6% at 5 μM) compared with berberine on gluconeogenesis in rat primary hepatocytes. Additionally, these compounds significantly up-regulated the phosphorylation of AMPK and its substrate, acetyl-CoA carboxylase (ACC) and slightly decreased the mitochondrial membrane potential in L6 myotube cells. [ABSTRACT FROM AUTHOR]

Mitochondria-targeting theranostic probes that enable the simultaneously reporting of and triggering of mitochondrial dysfunctions in cancer cells are highly attractive for cancer diagnosis and therapy. Three fluorescent mitochondria-targeting theranostic probes have been developed by linking a mitochondrial dye, coumarin-3-carboximide, with a widely used traditional Chinese medicine, artemisinin, to kill cancer cells. Fluorescence images showed that the designed coumarin-artemisinin conjugates localized mainly in mitochondria, leading to enhanced anticancer activities over artemisinin. High cytotoxicity against cancer cells correlated with the strong ability to accumulate in mitochondria, which could efficiently increase the intracellular reactive oxygen species level and induce cell apoptosis. This study highlights the potential of using mitochondria-targeting fluorophores to selectively trigger and directly visualize subcellular drug delivery in living cells. [ABSTRACT FROM AUTHOR]

A series of novel berberine derivatives, 4,7,12,12a-tetrahydro-5 H -thieno[3′,2’:3,4]pyrido[1,2- b ]isoquinolines was designed, synthesized, and biologically evaluated for their anti-diabetic activity. Following the evaluation in two types of cells, compounds 4aa , 4bq , and 4bv stimulated glucose consumption (1.8- to 2.3-fold), reduced gluconeogenesis (60–85%), inhibited mitochondria respiratory chain complex I and activated AMPK indirectly. In a db / db mice model, compounds 4bq and 4bv lowered fasting blood glucose at a dose of 120 mg/kg/day. In addition, compounds 4bq and 4bv were found to possess improved pharmacokinetic profiles (bioavailability 45 and 106%, respectively) compared to berberine. Compounds 4bq and 4bv exhibited no obvious hERG inhibition (IC 50 > 10 μM). [ABSTRACT FROM AUTHOR]

This review provides a brief assessment of the methodological field of trifluoromethylation and its possible impact on the development of new CF 3 -containing pharmaceuticals. Structural aspects of five new drug-candidates, [tafenoquine (aromatic CF 3 ), roniciclib (heteroaromatic CF 3 ), BAY-38-7271 (aliphatic CF 3 ), sonidegib (O CF 3 ) and navitoclax (S-CF 3 )] currently under the development in phase II and III clinical studies, and their biological properties, therapeutic area and synthesis are critically discussed. [ABSTRACT FROM AUTHOR]

Psoriasis is a kind of chronic inflammatory skin disorder, while the long-term use of conventional therapies for this disease are limited by severe adverse effects. Novel small molecules associated with new therapeutic mechanisms are greatly needed. It is known that phosphodiesterase 4 (PDE4) plays a central role in regulating inflammatory responses through hydrolyzing intracellular cyclic adenosine monophosphate (cAMP), making PDE4 to be an important target for the treatment of inflammatory diseases (e.g. psoriasis). In our previous work, we identified a series of novel PDE4 inhibitors with a tetrahydroisoquinoline scaffold through structure-based drug design, among which compound 1 showed moderate inhibition activity against PDE4. In this study, a series of novel tetrahydroisoquinoline derivatives were developed based on the crystal structure of PDE4D in complex with compound 1. Anti-inflammatory effects of these compounds were evaluated, and compound 36, with high safety, permeability and selectivity, exhibited significant inhibitory potency against the enzymatic activity of PDE4D and the TNF-α release from the LPS-stimulated RAW 264.7 and hPBMCs. Moreover, an in vivo study demonstrated that a topical administration of 36 achieved more significant efficacy than calcipotriol to improve the features of psoriasis-like skin inflammation. Overall, our study provides a basis for further development of tetrahydroisoquinoline-based PDE4 inhibitors against psoriasis. Image 1 • 51 tetrahydroisoquinolines derivatives as novel PDE4 inhibitors were designed, synthesized and evaluated. • The optimum compound 36 exhibited high safety, potency, permeability and selectivity in vitro. • The crystal structure of PDE4D in complex with compound 36 was solved. • Compound 36 exhibited superior therapeutic efficacy than calcipotriol against the IMQ-induced murine psoriasis-like skin inflammation. [ABSTRACT FROM AUTHOR]