Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

The synthesis of 6-deazaformycin A

The synthesis of the new C-nucleoside 6-deazaformycin A was achieved through the condensation of a suitably substituted lithiated 2-picoline with 2,3,5-tri-O-benzyl-d-ribonolactone, borohydride reduction of the resulting hemiacetals, followed by intramolecular Mitsunobu cyclization of the carbinols, manipulation of the protecting groups, and subsequent ring closure to result in the formation of 7-amino-3-(β-d-ribofuranosyl)pyrazolo[4,3-b]pyridine. © Georg Thieme Verlag Stuttgart

Synthesis and antiviral activity evaluation of some novel acyclic C-nucleosides

The preparation of novel 5-amino or 7-hydroxy substituted pyrazolo[4,3-b]pyridine and pyrazolo[3,4-c]pyridine acyclic C-nucleosides is described. Their synthesis was carried out by condensation of suitably substituted lithiated picolines with 2-benzyloxyethoxymethylchloride followed by pyrazole ring annulation. The compounds were evaluated for their antiviral activity against a wide panel of viruses, but were found inactive at subtoxic concentrations. © 2008 Pharmaceutical Society of Japan

The synthesis of the new C-nucleoside 6-deazaformycin B

The synthesis of the 6-deaza analogue of formycin B is described, through the condensation of lithiated 4-methoxy-2-methyl-3-trifluoroacetamidopyridine with a suitably protected ribonolactone, dehydration of the resulting hemiacetal, reduction and subsequent ring closure followed by protecting group manipulation. © Georg Thieme Verlag Stuttgart

Synthesis of new nebularine analogues and their inhibitory activity against adenosine deaminase

A number of new 2,6-disubstituted-1-deazanebularine analogues as well as two structurally related pyrazole-fused tricyclic nucleosides were prepared. Their synthesis was carried out by the conversion of 6-amino-2-picoline to a suitable 1-deazapurine, followed by a Vorbrüggen type glycosylation and subsequent elaboration of the condensed pyrazole ring. The synthesized nebularine analogues proved to be weak adenosine deaminase inhibitors. © 2015 The Pharmaceutical Society of Japan

Design, synthesis and cytotoxic activity evaluation of new aminosubstituted benzofurans

A number of new aminosubstituted benzofuran analogues have been prepared and their cytotoxic/cytostatic activity was investigated against five human tumor cell lines (MCF-7, SKBR3, SKOV3, HCT-116 and HeLa). Certain compounds showed noticeable tumor cell growth inhibition, indicative of possible structure-Activity relationships. © 2014 Bentham Science Publishers

New bioactive 5-arylcarboximidamidopyrazolo[3,4-c]pyridines: Synthesis, cytotoxic activity, mechanistic investigation and structure-activity relationships

In this study, a series of novel substituted pyrazolo[3,4-c]pyridin-5-ylamidines was synthesized and their cytotoxicity against three cancer cell lines (MDA-MB-231, HT-1080, PC-3), as well as a human normal cell line (AG01523) was evaluated. A number of derivatives could strongly reduce cancer cells proliferation and exhibit apoptotic induction capability, while reasonable structure-activity relationships could be extracted. Certain analogues were endowed with low toxicity against normal cells. Cell cycle analysis revealed that most of the active compounds induced a G0/G1 arrest of HT-1080 cells. Moreover, the potential mechanisms of the cytotoxic activity of the promising compounds were investigated in HT-1080 cells, upon study of their effects on the phosphorylation of Akt, ERK and p38 MAPK. Most of the active derivatives inhibit phosphorylation of Akt and ERK and/or induce p38 MAPK phosphorylation, providing a potential indication on the mode of action of this class. © 2021 Elsevier Masson SA

The application of Mitsunobu cyclization for the synthesis of 2′,3′-dideoxy-C-nucleosides designed as didanosine analogues

The synthesis of new 2′,3′-dideoxy-C-nucleosides structurally related to didanosine has been achieved. Their preparation involved condensation of a suitably substituted, lithiated 2- or 4-picoline with 2′,3′- dideoxy-5′-benzylribonolactone, followed by borohydride reduction of the resulting hemiacetals, intramolecular Mitsunobu cyclization of the derived diols, formation of the pyrazolo[3,4-c] or [4,3-b]pyridine ring-system and subsequent removal of the protecting groups. © Georg Thieme Verlag Stuttgart

Design, synthesis and anti-HBV activity evaluation of new substituted imidazo[4,5-b]pyridines

The design and synthesis of a number of new imidazo[4,5-b]pyridines is described. The heterocyclic scaffold possesses 6-chloro- or 5,6-dichloro-substitution and bears various 2-alkylamino-methyl or ethyl groups. The corresponding N1 and N3-tosylates are also presented. The anti-HBV activity of the compounds was evaluated in HBV infectious system at the level of HBV rcDNA secretion and CC50, EC50 and selectivity index values were determined. The tosylates showed low antiviral potency and relatively high cytotoxicity, on the contrary, a number of 2,5 and/or-6-substituted imidazopyridines, mainly those belonging to the 6-chloroimidazo[4,5-b]pyridine series, were endowed with a very interesting profile and were further investigated. The most promising among them, along with the reduction of the secreted HBV rcDNA, also caused a reduction in HBV cccDNA and pgRNA levels, with a concomitant accumulation of the intracellular encapsidated rcDNA. Surprisingly, the most active 2-diethylaminoethyl-substituted derivative (21d), was highly competitive to interferon. © 2020 Elsevier Inc

Novel Substituted Purine Isosteres: Synthesis, Structure-Activity Relationships and Cytotoxic Activity Evaluation

A number of pyrrolo[2,3-c]pyridines, pyrrolo[3,2-d]pyrimidines and pyrazolo[4,3-d]pyrimidines were designed and synthesized as antiproliferative agents. The target compounds possessed selected substituents in analogous positions on the central scaffold that allowed the extraction of interesting SARs. The cytotoxic activity of the new derivatives was evaluated against prostatic (PC-3) and colon (HCT116) cell lines, and the most potent analogues showed IC50 values in the nM to low µM range, while they were found to be non-toxic against normal human fibroblasts (WI-38). Flow cytometric analysis of DNA content revealed that the most promising derivative 14b caused a statistically significant accumulation of PC-3 cells at G2 /M phase and induced apoptosis in PC-3 cells. © 2021 by the authors. Licensee MDPI, Basel, Switzerland