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Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment. [ABSTRACT FROM AUTHOR]

The Lemieux-Johnson oxidation was employed for the cleavage of the carbon-carbon double bond of shikimic acid derivatives. Through this procedure, a series of the sixteen novel (2 S,3 S,4 R)-2,3,4,7-tetrahydroxy-6-oxoheptanals bearing three contiguous stereocentres have been synthesized in excellent yields. [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription-3 (STAT3) is the most studied member from seven latent cytoplasmatic transcription factors (STATs 1-4, 5a, 5b and 6) that are closely associated with the occurrence of many types of cancer (breast, leukemia, lung, lymphoma, ovarian and prostate). STAT3 contains four functional domains, from which the Src homology 2 domain (SH2 domain) is the major target for inhibition of these proteins. Inhibition results in STAT3 tyrosine 705 (Y705) phosphorylation, dimerization, nuclear transport, DNA binding and transcription induction. The benzo[b]thiophene 1,1-dioxide (BTP) as a pharmacophore is part of many STAT3 inhibitors, such as Stattic, HJC0123, HJC0149 and HJC0416 (1,2,3). Stattic (6-nitro derivate of BTP) is a small molecule which selectively inhibited STAT3 SH2 domain function in vitro (3). HJC0123, HJC0149 and HJC0416 are carboxamides made from 6-amino derivate of BTP and substituted aromatic carboxylic acids (1,2). In this study we have in silico designed, synthesized and purificated 8 new Stattic-carboxamides. Their physical chemical properties were predicted in silico and then experimentally evaluated. Their biological activity was tested on murine and human cancer cell lines. Results were evaluated and compared to Stattic as a reference compound. [ABSTRACT FROM AUTHOR]

Nerve agents are organophosphorus compounds (OPs) with very potent toxicity due to their irreversible inhibition of the essential enzymeacetylcholinesterase (AChE; EC 3.1.1.7), which is primarily important in the control of neurotransmission in synapses. The related enzyme butyrylcholinesterase (BChE; EC 3.1.1.8) is inhibited by OPs aswell. Compounds with an oxime group act as reactivatorsof the inhibited AChE by the nucleophilic displacement of OP moiety from the enzyme's catalytic serine and are used as a pharmacological treatment after OP poisoning. However, restoration of the AChE activity is directly related to the oxime structure and standard oximes in medical practice are not equally effective for various OPs (1). It was demonstrated that the chlorine substituent reduce the pKa of the oxime group compared to the non-substituted analogues and result in the higher formation of oximate anion which can be correlated to their increased reactivation ability (2). In this work, the synthesis and thorough evaluation of fluorinated and chlorinated oximes is presented. Firstly, their stability and oximate forming properties (pKa) were determined. Further, the evaluation comprised testing for affinity for human recombinant AChE and human purified plasmatic BChE, the oxime's efficacy in reactivation of sarin-, cyclosarin-, VX-, tabun-inhibited AChE or BChE. Finally, the antidotal potential of the lead halogenated oxime was tested in mice exposed to sarin and cyclosarin (3). [ABSTRACT FROM AUTHOR]

Malaria is annually responsible for more than 400 thousands causalties. The disease is transmitted via infected female Anopheles mosquitoes. Spread of the malaria can be prevented by using either chemical compounds known as insecticides or by genetically engineered plants.[1,2] Mechanism of action of currently deployed insecticide involves inactivating acetylcholinesterase (AChE, EC 3.1.1.7) enzyme by binding to Ser360 (Anopheles gambiae numbering). More recently, Cys447 located close to active site entrance was emerged as an alternative target to overcome insecticide resistance and also improving selectivity towards insect AChE over mammalian one.[3] In our contribution, we have developed novel, straightforward and facile synthesis for Cys-targeted insecticides containing either maleimide or succinimide scaffolds. Employment of Grubbs olefin metathesis allowed us to obtain the final compounds in multistep synthesis in relatively high yields. We propose that the described synthetic route might be used in large scale-up for further studies. [ABSTRACT FROM AUTHOR]