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Argininosuccinate synthase (ASS1) is a ubiquitous enzyme in mammals that catalyzes the formation of argininosuccinate from citrulline and aspartate. ASS1 genetic deficiency in patients leads to an autosomal recessive urea cycle disorder citrullinemia, while its somatic silence or down-regulation is very common in various human cancers. Here, we show that ASS1 functions as a tumor suppressor in breast cancer, and the pesticide spinosyn A (SPA) and its derivative LM-2I suppress breast tumor cell proliferation and growth by binding to and activating ASS1. The C13-C14 double bond in SPA and LM-2I while the Cys97 (C97) site in ASS1 are critical for the interaction between ASS1 and SPA or LM-2I. SPA and LM-2I treatment results in significant enhancement of ASS1 enzymatic activity in breast cancer cells, particularly in those cancer cells with low ASS1 expression, leading to reduced pyrimidine synthesis and consequently the inhibition of cancer cell proliferation. Thus, our results establish spinosyn A and its derivative LM-2I as potent ASS1 enzymatic activator and tumor inhibitor, which provides a therapeutic avenue for tumors with low ASS1 expression and for those non-tumor diseases caused by down-regulation of ASS1., Arginine addiction induced by argininosuccinate synthase (ASSN1) deficiency has been exploited to treat ASS1-deficient cancers. Here, the authors show an alternative therapeutic approach where ASS1 activity is increased by the pesticide spinosyn A and is shown to inhibit breast cancer cell proliferation.

The first examples of enantiopure catalysts that are chiral merely due to coordination of different metal ions at enantiotopic positions of an achiral meso-ligand are reported. These catalysts exhibit a pseudo-Cs symmetry and are able to catalyze reactions demanding simultaneous involvement of two catalytic sites. The latter was demonstrated by application in the asymmetric ring-opening of meso-epoxides.

A convenient Fe-catalyzed four-component radical dual difunctionalization and ordered assembly of two alkenes with aromatic/aliphatic aldehydes and TBHP to provide chain elongated β,δ-functionalized ketones via a one-pot procedure has been developed. Aldehydes were homolytically cleavaged to produce acyl radicals and subsequently allowed for the successive construction of C(sp2)-C(sp3), C(sp3)-C(sp3), and C(sp3)-O bonds via dual radical insertions and radical-radical coupling, following the intrinsic nucleo/electrophilic reactivity of both the radicals and alkenes.

A convenient Co-catalyzed three-component decarbonylative alkylative esterification of styrene derivatives with aliphatic aldehydes and iodobenzene diacetate to provide chain elongated acetates and benzoates has been developed. Readily available aliphatic aldehydes are decarbonylated into 1°, 2° and 3° alkyl radicals for the construction of a C(sp3)–C(sp3) bond via radical addition and an interconversion of CoII–CoIII–CoI complexes is accountable for the formation of a C(sp3)–O bond.

Background: The heptaprotective flavonolignan silibinin and dehydrosilibinin have exhibited moderate antiproliferative activities toward many cancer cell lines. Considering of the nontoxic profile of these natural products, chemical modification to enhance the anticancer potentials is promising. Method: A series of 7-O-aminoalkyl-2,3-dehydrosilibinin derivatives were synthesized and evaluated for their antiproliferative activities against several cancer cell lines. Results: A number of the synthesized dehydrosilibinin derivatives exhibited greatly enhanced potency with 50% growth inhibition at low micromolar concentrations. Structure activity study indicated that the distance between N and 7-O on the side chain has a limited influence on the antiproliferative activity, while the presence of a morpholino group decreases the antiproliferative activities dramatically. Flow cytometry based assays on human colon cancer HCT116 cells revealed that 6a and 6c, two of the most potent derivatives, effectively arrested the cell cycle in the G2 phase and stimulated cell apoptosis. Conclusion: Our findings suggest that attaching an appropriate tertiary amino alkyl side chain through 7-Oalkylation on 2,3-dehydrosilibinin, would be a viable strategy for the development of silibinin derivatives as anticancer agents.

Natural quinones and their analogues have attracted growing attention because of their novel anticancer activities. A series of novel isothiazoloquinoline quinone analogues were synthesized and evaluated for antitumor activities against four different kind of cancer cells. Among them, isothiazoloquinolinoquinones inhibited cancer cells proliferation effectively with IC50 values in the nanomolar range, and isothiazoloquinolinoquinone 13a induced the cell apoptosis. Further exploration of possible mechanism of action indicates that 13a not only activates ROS production through NQO1-directed redox cycling but also inhibits the phosphorylation of STAT3. These findings indicate that 13a has potential use for the development of new skeleton drug candidate as an efficient substrate of NQO1 and STAT3 inhibitor.

In order to enhance the mitochondria-targeting ability of spinosad. A series of quartenary ammonium spinosyn derivatives was designed and synthesized. Some of the derivatives displayed greatly enhanced antiproliferative ability towards tested human cancer cell lines. The structure activity relationship study indicated that lipophilicity has a great influence on the antiproliferative effects of these derivatives. The most active compound 11d exhibited remarkably enhanced OXPHS inhibition and apoptosis inducing ability than spinosyn A.

A practical zinc acetate dihydrate catalyzed reductive amination of various carbonyl compounds with DMF as Me2N source, reductant and solvent is developed. This reaction shows broad substrate scope, good functionality tolerance, avoids pressure-proof reactor and column chromatograph isolation with up to 98 % yield, to make it an attractive method for the preparation of N,N-dimethyl tertiary amines.

An efficient approach for integrin-targeting cRGDfK conjugate synthesis has been developed using a new protected cyclopentapeptide, cR(NO2)GD(Bn)fK(Fmoc), as the key intermediate. cR(NO2)GD(Bn)fK(F...

In order to improve the antiproliferative activity of naringenin, a naturally occurred flavonoid in citrus fruits, a series of naringenin derivatives with a tertiary amino side chain were prepared. The antiproliferative activities of these naringenin derivatives were evaluated on four human cancer cell lines, namely, MCF-7, HCT116, Hela, and A549. Compounds 4a, 9a, and 10a exhibited remarkably enhanced growth inhibition activity. Based on the observed results, the structure–activity relationship of these derivatives was discussed.

The synthesis of two conformationally restricted Cr(III) salen complexes, 2 and 3, is described. Together, they constitute a supramolecular hydrogen-bonding catalytic system for the recently reported asymmetric ring-opening reactions of epoxides by a dynamic supramolecular catalyst. The synthesis involves state-of-the art transformations in frontline synthetic chemistry applied to heterocyclic chemistry. Hence, palladium-catalyzed reactions were employed, including carbonylative annelation and Suzuki cross-coupling reactions, for the formation of one of the heterocyclic rings (quinolone) and the functionalization of the formed rings. For the construction of the second heterocyclic ring (isoquinolone), a Curtius rearrangement was employed. The corresponding salen ligands were then prepared by Schiff-base reactions, yielding the final complexes after metal insertion. For reference purposes the less conformationally restricted Cr(III) complexes 4 and 5 were also synthesized.

A series of DLC (delocalized lipophilic cation) modified spinosyn derivatives were synthesized and evaluated for antitumor efficacies both in vitro and in vivo. Cancer cell based antiproliferative assays indicated that the more lipophilic derivatives had stronger inhibitory effects on the tested cancer cell lines. Compound 7b and 8b exhibited strong anti-OXPHOS and apoptosis inducing ability. Notable antitumor efficacies of 7b (5 mg/kg) and 8b (2.5 mg/kg) were observed in the in vivo tumor xenograft experiments, however, lethal toxicities were observed on higher dosages. Our findings indicated that DLC modification is a viable strategy to enhance the anti-OXPHOS and antitumor efficacies of spinosyn derivatives.

An iodine-catalyzed multiple C–H bond functionalization of isoquinolines with methylarenes via a successive benzylic sp3 C–H iodination/N-benzylation/amidation/double sp2 C–H oxidation sequence is developed. This reaction utilizes un-functionalized isoquinolines and readily available methylarenes as starting materials, proceeds under metal-free conditions, and avoids a multi-step experimental operation, to make it an efficient and practical method for the synthesis of N-benzyl isoquinoline-1,3,4-triones.

Bimetallic catalysts have been synthesised based on Jacobsens C2-symmetric bissalen ligand. They constitute the first examples of compounds with pseuodo-C2 symmetry, owing to the presence of two different metal ions. They have been investigated in the ring-opening of meso-epoxides by trimethylsilyl azide (TMSN3). Pseudo-C2-symmetric [CrIII?Co]bissalen complexes were the best in inducing ee (9394?%) in the ring-opened product of cyclohexene oxide by TMSN3 under solvent-free conditions, whereas a pseudo-C2-symmetric [CrIII?MnIII]-bissalen complex displayed the highest turnover frequency (183 h-1) but induced a lower ee (66?%). A broad substrate scope was displayed by a pseudo-C2-symmetric [CrIII?Co]bissalen catalyst: at 0.1 mol?% catalytic loading and under solvent-free conditions, it induced the highest ee to date in the ring-opened product of a range of different meso-epoxides by using TMSN3. (Less)

Three stilbene tetramen, carasinols A-C (1–3), along with three known substances, leachianol C, cararosinol A and stenophyllol B, were isolated from the roots of Caragana sinica. Their structures were elucidated by spectroscopy. It was found that compounds isolated except for stenophyllol B stimulated the proliferation of cultured osteoblasts.

Angelmarin, a naturally occurring coumarin, exhibited highly anti-austerity potency towards human pancreatic carcinoma cell line PANC-1. In this paper, an efficient and eco-friendly synthesis of angelmarin and its analogs from columbianetin has been developed via a ZnO mediated esterification and a Wittig reaction.

A new tetrastilbene named carasinol D (1) was isolated from the roots of Caragana sinica. Its structure was elucidated by spectroscopic analysis. Compound 1 was obtained from carasinol B (2) by an acid-catalyzed conversion.

Rhodococcus erythropolis AJ270, a nitrile hydratase/amidase-containing microbial whole cell catalyst, is able to catalyze the hydrolysis of a number of β-hydroxy and β-alkoxy nitriles under very mild conditions. Both the efficiency and enantioselectivity of the biocatalysis, however, were strongly dependent upon the structures of both nitrile and amide substrates. When biotransformations of racemic 3-hydroxy-3-phenylpropionitrile and 2-hydroxymethyl-3-phenylpropionitrile gave low enantioselectivity, their O-methylated isomers underwent highly efficient and enantioselective biocatalytic reactions to afford highly enantioenriched β 2 - and β 3 -hydroxy amide and acid derivatives in excellent yield. The study has provided an example of simple and very convenient substrate engineering method to increase the enantioselectivity of the biocatalytic reaction.

Under very mild conditions, biotransformations of racemic azido nitriles using Rhodococcus erythropolis AJ270, a nitrile hydratase/amidase-containing microbial whole-cell catalyst, afforded highly enantiopure, (R)-α-arylmethyl- and (+)-α-cyclohexylmethyl-β-azidopropanoic acids and their (S)- and (−)-carboxamide derivatives in excellent yields. The resulting functionalized chiral organoazides were converted in a straightforward fashion to a pair of antipodes of α-benzyl-β-amino acids (R)-13 and (S)-13. Azido carboxamide (S)-11a and azido carboxylic acid (R)-12a underwent ‘click’ reactions with diethyl acetylenedicarboxylate and phenylacetylene to produce functionalized chiral triazoles 14 and 15, respectively. The easy preparation of the starting nitrile substrates, highly efficient and enantioselective biotransformation reactions, and versatile utility of the resulting functionalized azido carboxylic acids and amide derivatives, render this method very attractive and practical in organic synthesis.

[Structure: see text] Catalyzed by the Rhodococcus erythropolis AJ270 whole cell catalyst, the O-benzylated beta-hydroxy alkanenitriles underwent remarkably high enantioselective biotransformations, whereas the biotransformations of free beta-hydroxy alkanenitriles gave very low enantioselectivity. The easy manipulations of O-protection and O-deprotection, excellent chemical and enantiomeric yields of biotransformations, along with the scalability render this enzymatic transformation attractive and practical for the synthesis of highly enantiopure beta-hydroxy alkanoic acids and their amide derivatives.

Rhodococcus erythropolis AJ270, a nitrile hydratase/amidase-containing microbial whole cell catalyst, is able to catalyze the hydrolysis of a number of β-hydroxy and β-alkoxy nitriles under very mild conditions. Both the efficiency and enantioselectivity of the biocatalysis, however, were strongly dependent upon the structures of both nitrile and amide substrates. When biotransformations of racemic 3-hydroxy-3-phenylpropionitrile and 2-hydroxymethyl-3-phenylpropionitrile gave low enantioselectivity, their O-methylated isomers underwent highly efficient and enantioselective biocatalytic reactions to afford highly enantioenriched β 2 - and β 3 -hydroxy amide and acid derivatives in excellent yield. The study has provided an example of simple and very convenient substrate engineering method to increase the enantioselectivity of the biocatalytic reaction.