Camptothecin is a type of topo

Camptothecin is a type of topo I inhibitor, and its prodrugs irinotecan and topotecan have been approved by the FDA for clinical cancer treatment. It has been reported that SAHA can enhance the cytotoxicity of camptothecin derivatives in several cancer cell lines20., 21., 22., 23., 24.. Taking the synergy effect between HDAC inhibitors and camptothecin derivatives into account, we have designed a series of SN-38 prodrugs exhibit HDAC inhibition activity (Fig. 2). The hydroxamic Imeglimin sale moiety can work as the ZBG part so that the prodrugs can retain HDAC inhibition activity. Linkers can help with the regulation of the HDAC inhibition activity, and the cleavage of them will promote the release of the parent drug SN-38, which has great antiproliferative activity. A range of in vitro analyses have been used to identify the optimal chemical modification, which included substituted position and carbon chain length to establish the best prodrug that can effectively release the parent drug to exhibit great antiproliferative activity.
Results and discussion
Conclusions A series of camptothecin prodrugs exhibiting HDAC inhibition activity have been designed and synthesized based on the synergistic effect between camptothecin derivatives and HADC inhibitors. The evaluation included not only inhibition activity but also the stability of the compounds, which gave us a better understanding of them. With the modulation of linkers, the HDAC inhibition activity was maintained and the active drug can be released efficiently. Among these prodrugs, compound 21a showed great antiproliferative activity with IC50 values in the nanomolar range. The results of in vitro stability also confirmed the complete conversion from compound 21a to SN-38. And working together with the metabolism SN-38, the synergistic effect might occur. All of these factors made compound 21a a promising prodrug for cancer treatment.
Materials and methods
Acknowledgments We are grateful for the financial support for Shanghai Science and Technology Council (16DZ2280100).
Introduction Depression is a common mental disorder manifested by low mood, loss of interest or pleasure, decreased energy, feelings of guilt or low self-worth, disturbed sleep or appetite, poor concentration and anxiety symptoms [1]. According to the Global Burden of Disease (GBD) study [2] depressive disorders will become the second leading cause of disability worldwide by the year 2020 and a significant contributor to the burden of suicide and ischemic heart disease. The lifetime prevalence of depressive disorders is estimated to be approximately 17% in the United States, with a similar level being reported for European countries [3]. Depressive disorders often begin in adolescence and can become chronic or recurrent; thus, leading to substantial impairments in an individual’s ability to take care of his or her everyday responsibilities [4]. Because the etiology of depression is not fully understood, the development of useful diagnostic tests as well as highly effective and rapid-acting antidepressant treatment strategies has been very challenging [5]. A variety of environmental factors has been shown to contribute to mental disease, especially during the early stages of life. For example, exposure to chronic stress may result in permanent functional alterations in gene expression, inducing functional changes in the neural circuit, and consequently affecting behavior [6], [7]. Some of these alterations are known to be maintained by epigenetic modifications in specific brain regions [8], [9], [10], [11]. In general, epigenetics refers to covalent modification of DNA, protein, or RNA, resulting in alterations to the function and/or regulation of these molecules, without changing their primary sequences. In some cases, these modifications are stable and passed on to future generations, while in other situations they are dynamic and change in response to environmental stimuli. Epigenetic regulation is fundamental for many cellular (both physiological and pathological) processes and allow to explain some phenomena in which medical observations confront traditional genetics. The major mechanisms in epigenetic regulation include chemical modifications to the cytosine residues of DNA (DNA methylation; long-term changes) and histone proteins associated with DNA (histone modifications − HMs; more flexible and short-term changes) [12]. Out of many post-translational modifications of histone proteins that control the chromatin architecture around specific genes thereby regulating their transcription, histone acetylation and deacetylation are the best studied and most common forms of HMs in neuropsychiatric diseases [13], [14], [15], [16]. Overall, histone acetylation leads to the activation of the transcription machinery while deacetylation results in its inhibition. The key regulatory enzymes involved in these post-translational modifications are histone acetyltransferases (HATs) and histone deacetylases (HDACs) [17].