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The chapter titled “Eight-membered Rings with two Heteroatoms 1,2” deals with heterocine rings with two heteroatoms in a 1,2 relationship, namely 1,2-diazocine, 2H-1,2-oxazocine, 2H-1,2-thiazocine, 1,2-dioxocin, 1,2-oxathiocin and 1,2-dithiocin. This article covers the literature from 2007 to 2019 and reports the chemistry of uncondensed derivatives, heterocines fused to carbocycles and heterocycles, as well as bridged heterocines. As usual, in the case that a particular section is not mentioned, it means that no chemistry has been reported. In this article, the “Biosynthesis” paragraph was additionally introduced, since in the latest years the contribution of Nature to the synthesis of diheterocines became important, especially for biologically active compounds. Following this approach, the natural sources will be analyzed, as well as the biosynthetic pathway whenever available. In this edition, as happened in the previous one, the interest in 1,2-heterocines has been driven by the pharmacological activity shown by several derivatives or some potentially important industrial applications.

Introduction There are few effective therapies for malignant pleural mesothelioma (MPM), which remains one of the most lethal cancers. We previously demonstrated that low expression of the PCFT transporter, both at mRNA and protein levels, is associated with shorter survival of MPM patients treated with pemetrexed (Giovannetti et al., 2017). Since hypoxia has also been associated to antifolate-resistance (Raz et al, 2014), this study was aimed at elucidating key factors in pemetrexed resistance and hypoxia that may contribute to the rational development of novel therapeutic interventions against mesothelioma. Methods The levels of PCFT and of the hypoxia marker carbonic anhydrase-IX were determined by immunohistochemistry in tissue-microarrays of pemetrexed-treated patients. The contribution of PCFT expression and hypoxia on pemetrexed activity were evaluated in mesothelioma cells and spheroids, through siRNA-knockdown and PCR arrays. In vitro and in vivo studies on MPM cells and primary cultures from peritoneal mesothelioma (Deraco et al., 2010) evaluated the activity of novel lactate dehydrogenase-A (LDH-A) inhibitors (Granchi et al., 2011). Results The lowest PCFT levels were detected in tissues with the highest levels of the hypoxia marker carbonic anhydrase-IX. PCR-arrays of 84 genes (Hypoxia-RT2 ProfilerTM) in cells treated with PCFT-siRNA, spheroids and cells under hypoxic conditions demonstrated increased expression of LDH-A, which was successfully targeted by specific inhibitors both in vitro (especially when growing cells at O2 tension of 0.1%), and in novel in vivo orthotopic models, characterized by hypoxic regions, as also detected with high-frequency ultrasound and photoacoustic imaging. Discussion Our findings suggest that low PCFT expression, associated with pemetrexed-resistance, could stimulate the increased expression of LDH-A as a feedback mechanism. Within the cells an increase in acidity caused by LDH-A activity could indeed result in greater extracellular acidification and a strong protonguided force that would favor folate transport via PCFT, thereby linking folate transport with cell metabolism. Conclusion These results support a new therapeutic strategy targeting LDH-A in order to eradicate pemetrexedresistant mesothelioma cells characterized by low-PCFT. Bibliography - Deraco M, Baratti D, Cabras AD, Zaffaroni N, Perrone F, Villa R, Jocollè J, Balestra MR, Kusamura S, Laterza B, Pilotti S. Experience with peritoneal mesothelioma at the Milan National Cancer Institute. World J Gastrointest Oncol. 2010;2(2):76-84. - Giovannetti E, Zucali PA, Assaraf YG, Funel N, Gemelli M, Stark M, Thunnissen E, Hou Z, Muller IB, Struys EA, Perrino M, Jansen G, Matherly LH, Peters GJ. Role of proton-coupled folate transporter in pemetrexed resistance of mesothelioma: clinical evidence and new pharmacological tools. Ann Oncol. 2017;28(11):2725-2732. - Granchi C, Roy S, Giacomelli C, Macchia M, Tuccinardi T, Martinelli A, Lanza M, Betti L, Giannaccini G, Lucacchini A, Funel N, Giovannetti E, Peters GJ, Palchaudhuri R, Calvaresi EC, Hergenrother PJ, Minutolo F. Discovery of N-hydroxyindole-based inhibitors of human lactate dehydrogenase isoform A) as starvation agents against cancer cells. J Med Chem. 2011;54(6):1599-612. - Raz S, Sheban D, Gonen N, Stark M, Berman B, Assaraf YG. Severe hypoxia induces complete antifolate resistance in carcinoma cells due to cell cycle arrest. Cell Death Dis. 2014;5:e1067.

The concept of protein kinase inhibition starts from the groundbreaking research on the role of these proteins in the regulation of fundamental processes, including proliferation, cell cycle, apoptosis, metabolism, and inflammation. Kinase genetic mutations, as well as overexpression and dysregulation, can contribute to the development of several diseases, including neoplasms, leading to relapses and resistance to standard drug chemotherapy [1-3].

The enzyme glutaminase-1 (GLS-1) has shown a clear and coherent implication in the progression and exacerbation of different aggressive tumors such as glioblastoma, hepatocarcinoma, pancreas, bone, and triple-negative breast cancer. Few chemotypes are currently available as selective GLS-1 inhibitors, and still, fewer of them are at the clinical stage. In the present paper, starting from a naturally-inspired antitumor compound library, metabolomics has been used to putatively identify the molecular mechanism underlying biological activity. GLS-1 was identified as a potential target. Biochemical analysis confirmed the hypothesis leading to the identification of a new hit compound acting as a GLS-1 selective inhibitor (IC50 = 3.96 ± 1.05 μM), compared to the GLS-2 isoform (IC50 = 12.90 ± 0.87 μM), with remarkable antitumor potency over different aggressive tumor cell lines. Molecular modelling studies revealed new insight into the drug-target interaction providing robust SAR clues for the rational hit-to-lead development. The approach undertaken underlines the wide potential of metabolomics applied to drug discovery, particularly in target identification and hit discovery following phenotype screening.

This chapter titled “Eight-membered Rings with two Heteroatoms 1,5” deals eight-membered rings with two heteroatoms in a 1,5-relationship, namely 1,5-diazocine, 1,5-oxazocine, 1,5-thiazocine, 1,5-dioxocin, 1,5-oxathiocin, and 1,5-dithiocin and covers the literature from 2007 to October 2020 (SciFindern search) reporting the chemistry of uncondensed derivatives, diheterocines fused to carbocycles and heterocycles, as well as bridged diheterocines. Among them, the 1,5-diazocine ring system is by far the largest class, based on the number of publications which constituted the 87% of the total amount of the references reported in the range of interest of CHEC IV. Thus, 1,5-diazocines were divided in three different sub-chapters: Tröger's bases and related compounds, bispidines and related compounds and other uncondensed and fused 1,5-diazocines. The main change in this chapter, with respect to CHEC-III, is related to “Experimental Structural Methods” paragraph in which it was avoided reporting the spectroscopic data (NMR, IR, UV etc.) as in the previous edition they were extensively provided and, in the latest period, they remained in the same range. Analogously, the same behavior was maintained for physical properties (solubility, melting points, chromatographic behavior, conformational issues) thanks to the coverage in “Thermodynamic Aspects” paragraph of CHEC-III, which remained substantially unchanged to-date. Actually, in this edition, the inclusion of a paragraph on biosynthesis was envisaged since Nature, in recent years, has made a significant contribution to the synthesis of secondary metabolites, especially for biologically active ones. However, no 1,5-diheterocine derivative has been reported to be synthesized by Nature. In this chapter, as happened in the previous CHEC editions, the interest in 1,5-diheterocines has been driven by the pharmacological activities shown by several derivatives or some potentially important industrial applications.

Introduction: Despite clinical efforts, pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The scarcity of effective therapies can be reflected by the lack of reliable biomarkers to adapt anticancer drugs prescription to tumors’ and patients’ features. Areas covered: Pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best matches individual and tumor genetic profile, but it has not yet led to gains in outcome. This review describes PDAC pharmacogenetics findings, critically reappraising studies on polymorphisms and -omics profiles correlated to response to gemcitabine, FOLFIRINOX, and nab-paclitaxel combinations, as well as limitations of targeted therapies. Further, we question whether personalized approaches will benefit patients to any significant degree, supporting the need of new strategies within well-designed trials and validated genomic tests for treatment decision-making. Expert opinion: A major challenge in PDAC is the identification of subgroups of patients who will benefit from treatments. Minimally-invasive tests to analyze biomarkers of drug sensitivity/toxicity should be developed alongside anticancer treatments. However, progress might fall below expectations because of tumor heterogeneity and clonal evolution. Whole-genome sequencing and liquid biopsies, as well as prospective validation in selected cohorts, should overcome the limitations of traditional pharmacogenetic approaches.

A new series of imidazo[2,1-b][1,3,4]thiadiazole derivatives was efficiently synthesized and screened for their in vitro antiproliferative activity on a panel of pancreatic ductal adenocarcinoma (PDAC) cells, including SUIT-2, Capan-1 and Panc-1. Compounds 9c and 9l, showed relevant in vitro antiproliferative activity on all three pre-clinical models with half maximal inhibitory concentration (IC50) ranging from 5.11 to 10.8 &micro, M, while the compounds 9e and 9n were active in at least one cell line. In addition, compound 9c significantly inhibited the migration rate of SUIT-2 and Capan-1 cells in the scratch wound-healing assay. In conclusion, our results will support further studies to increase the library of imidazo [2,1-b][1,3,4] thiadiazole derivatives for deeper understanding of the relationship between biological activity of the compounds and their structures in the development of new antitumor compounds against pancreatic diseases.

This review deals with 1,5-diheterocines that exhibited biological properties and covers comprehensively the literature from 2007 to the end of February 2019. Among the six possible heterocyclic systems belonging to the eight-membered rings with two heteroatoms, N, O, and S, five had derivatives showing pharmacological activities: 1,5-diazocines, 1,5-oxazocines, 1,5-thiazocines, 1,5-dioxocins, and 1,5-dithiocins. Instead, literature reported no articles dealing with 1,5-oxathiocins of interest in medicinal chemistry. In addition to uncondensed derivatives, 1,5-diheterocines fused to five- and six-membered carbocycles or heterocycles are covered. Bridged 1,5-diheterocines are covered as well.

Bacterial strains responsible for antibiotic resistant infections are increasing in an alarming way and the evolution of resistance mechanisms seems to be unstoppable. In the past decade, many efforts have been made in order to counteract this phenomenon but very few compounds have reached clinical trials. The development of new classes of antibiotics able to overcome the main bacterial drug resistance mechanisms is urgently required to counter the imminent danger of a postantibiotic era.

There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymatic inhibitors, such as the derivatives of the β-lactamase inhibitor avibactam, are closer to the clinic than other molecules. For example, MK-7655, in combination with imipenem, is in clinical development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addition, other molecules targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.

Humulus lupulus (Hop) contains numerous metabolites with anticancer potential. Despite this, their immunomodulatory activity, and in particular of bitter acids, is unknown. In this study, we demonstrated that a Hop pellet extract fraction containing bitter acids possesses immunomodulatory activity by enhancing Natural Killer (NK) cells function. After fractionation by semi-preparative Liquid Chromatography, three different fractions were obtained. The phytocomplex and the fractions were tested to verify the ability to modulate the NK compartment. Cytofluorimetric analysis revealed that a fraction containing bitter acids was able to up-regulate of NKG2D and NKp44 activating receptors. A further simplification yield a fraction mainly composed by Humulinones and Cohulupone derivatives, that at the concentration of 0.1 µg/mL induced selective activation of Nkp44 receptor and enhanced the cytolytic activity of NK cells against leukemia cell line K562. Those results point out the possible use of Hop bitter acids as natural immunostimulants and adjuvants in chemotherapy protocols.

Heterocyclic rings are recognized as key components of many natural, semi-synthetic and synthetic molecules with a broad spectrum of biological activities. Among these molecules, the indole and imidazo[2,1-b][1,3,4]thiadiazole systems have recently been described as useful scaffolds for the design of anticancer agents. Herein the antitumor activity of a series of 3-(6-phenylimidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1H-indoles, designed as hybrid structures, was assessed. Seven out of 10 compounds (1a-g) were submitted to National Cancer Institute (NCI). Remarkably, compound 1g showed antiproliferative activity against the full panel of sixty human cancer lines, with half-maximal inhibitory concentration of between 1.67 and 10.3 μM. Further studies showed antiproliferative activity of 1a-g and of three additional compounds 1h, 1i and 1l, with different substituents on the indole nucleus and phenyl ring, against three pancreatic cancer cell lines. In particular, derivatives 1g and 1h inhibited both proliferation and migration of SUIT-2 cells at concentrations lower than 10 μM. In conclusion, new indole derivatives are characterized by in vitro antitumor activity, supporting future mechanistic studies.

A series of 22 derivatives of the [1,2]oxazolo[5,4-e]isoindole system were synthesized through an efficient and versatile procedure that involves the annelation of the [1,2]oxazole moiety to the isoindole ring, producing derivatives with a wide substitution pattern. The structure-activity relationship indicates that the N-4-methoxybenzyl group appears crucial for potent activity. In addition, the presence of a 6-phenyl moiety is important and the best activity is reached with a 3,4,5-trimethoxy substituent. The most active compound, bearing both the structural features, was able to inhibit tumor cell proliferation at nanomolar concentrations when tested against the full NCI human tumor cell line panel. Interestingly, this compound was effective in reducing in vitro and in vivo cell growth, impairing cell cycle progression and inducing apoptosis, as a consequence of the inhibition of tubulin polymerization, in experimental models of diffuse malignant peritoneal mesothelioma (DMPM), a rapidly lethal disease, poorly responsive to conventional therapeutic strategies.

The synthesis, the antitumor activity, the SAR and, whenever described, the possible mode of action of 1,2,4-triazine derivatives, their N-oxides, N,. N'-dioxides as well as the benzo- and hetero-fused systems are reported. Herein are treated derivatives disclosed to literature from the beginning of this century up to 2016. Among the three possible triazine isomers, 1,2,4-triazines are the most studied ones and many derivatives having remarkable antitumor activity have been reported in the literature and also patented reaching advanced phases of clinical trials.

This review covering literature reports from the beginning of this century to 2016 describes the synthetic pathways, the antitumor activity, the structure-activity relationship and, whenever reported, the possible mechanism of action of 1,3,5-triazine derivatives as well as of their hetero-fused compounds. Many 1,3,5-triazine derivatives, both uncondensed and hetero-fused, have shown remarkable antitumor activities and some of them reached clinical development.

1,2,3-Triazines are a class of biologically active compounds that exhibit a broad spectrum of activities, including antibacterial, antifungal, antiviral, antiproliferative, analgesic and anti-inflammatory properties. This review, which covers the literature from the end of last century to 2016, treats, through a comprehensive, systematic approach, the 1,2,3-triazine and related benzo- and hetero-fused derivatives possessing antitumor activity. Their efficacy, combined with a simple synthesis confers to these molecules a great potential as scaffold for the development of antitumor compounds.

A new series of thiazole nortopsentin analogues was conveniently synthesized with fair overall yields. The antiproliferative activity of the new derivatives was tested against different human tumor cell lines of the NCI full panel. Four of them showed good antitumor activity with GI(50) values from micro to nanomolar level. The mechanism of the antiproliferative effect of these derivatives, was pro-apoptotic, being associated with externalization of plasma membrane phosphatidylserine and DNA fragmentation. The most active and selective of the new thiazoles confined viable cells in G2/M phase and markedly inhibited in vitro CDK1 activity. (C) 2017 Elsevier Masson SAS.

Background: Isoindolo[2,1-alpha] quinoxalines constitute an important class of compounds which demonstrated potent antiproliferative activity against different human tumor cell lines and topoisomerase I inhibitors. In particular, their water soluble imine or iminium salts recently synthesized showed potent growth inhibitory effect on NCI-60 tumor cell line panel and biological studies performed on the most active compounds demonstrated that they cause DNA damage via topoisomerase I poisoning. Objective: Herein, we investigate with molecular modeling methods, the common features responsible for topoisomerase I inhibition of the water-soluble isoindolo[2,1-alpha] quinoxalin-6-imines, by comparing them with known inhibitors. Methods: Different X-ray crystallographic structures with co-crystallized inhibitors were investigated and their binding modes were analyzed. The structures of the inhibitors were also compared through a pharmacophore analysis. As a validation of our docking method, the co-crystallized inhibitors were re-docked. Conclusion: Our docking studies performed on Isoindolo[2,1-alpha] quinoxalines and other inhibitors revealed very important common features responsible for topoisomerase I inhibition that can improve the design of new inhibitors.

A series of substituted 1-(5-bromopyridin-2-yl)-3-[2-(isoindolo[2,1-a]quinoxalin-6- ylamino)ethyl]thiourea and 1-(5-bromopyridin-2-yl)-3-[2-(6-iminoisoindolo[2,1-a]quinoxalin- 5(6H)-yl)ethyl]thiourea derivatives were prepared in good yields (63-85%) by reaction between the corresponding amino compounds with 5-bromo-2-isothiocyanatopyridine. All thiourea derivatives, tested for inhibition of HIV-1 RT, showed no significant antiviral activity.

Derivatives of the new ring systems bispyrido[4',3':4,5]pyrrolo[1,2-a:1',2'-d] pyrazine-6,13-dione and its deaza analogue pyrido[4'',3'':4',5']pyrrolo-[1',2':4,5]pyrazino [1,2-a]indole-6,13-dione were conveniently synthesized through a four-step sequence. Symmetrical derivatives of the former ring system were obtained through self condensation. On the other hand, condensation of 6-azaindole carboxylic acid with indole 2-carboxylic acid afforded the deaza analogue ring system. Derivatives of the title ring system were tested by the National Cancer Institute (Bethesda, MD, USA) and four of them exhibited modest activity against MCF7 (a breast cancer cell line) and/or UO-31 (a renal cancer cell line).

The synthesis of a novel class of tetrahydropyrrolo[3,4-g]indazoles is reported, by annelation of the pyrazole ring on the isoindole moiety by means of 5-hydroxymethylene tetrahydroisoindole-4-ones key intermediates, with good regioselectivity. Dihydroderivatives were also obtained by oxidation with DDQ of the corresponding tetrahydropyrrolo[3,4-g]indazoles. The growth inhibitory effect was evaluated at the National Cancer Institute of Bethesda and some derivatives showed modest activity.

2,5-bis(3′-Indolyl)pyrroles, analogues of the marine alkaloid nortopsentin, were conveniently prepared through a three step procedure in good overall yields. Derivatives 1a and 1b exhibited concentration-dependent antitumor activity towards a panel of 42 human tumor cell lines with mean IC50 values of 1.54 μM and 0.67 μM, respectively. Investigating human tumor xenografts in an ex-vivo clonogenic assay revealed selective antitumor activity, whereas sensitive tumor models were scattered among various tumor histotypes.

We have designed and synthesized isonetropsin and its one pyrrole unit analogue in which the amine and carbonyl groups have been switched in positions 2 and 4, respectively instead of 4 and 2 positions of the natural antibiotic netropsin.

Pyrrolo[3′,2′:6,7]cyclohepta[1,2-b]pyridines were synthesized as a new class of tricyclic system in which the pyridine ring is annelated to a cycloheptapyrrole scaffold, with the aim of obtaining new photosensitizing agents with improved antiproliferative activity and lower undesired toxic effects. A versatile synthetic pathway was approached, which allowed the isolation of derivatives of the title ring system with a good substitution pattern on the pyrrole moiety. Photobiological studies revealed that the majority of the new compounds showed a potent cytotoxic effect upon photoactivation with light of the proper wavelength, especially when decorated with a 2-ethoxycabonyl group and a N-benzyl substituted moiety, with EC50 values reaching the submicromolar level. The mechanism of action was evaluated.

A new series of pyrrolo[3′,2′:6,7]cyclohepta[1,2-d]pyrimidin-2-amines, was conveniently prepared using a versatile and high yielding multistep sequence. A good number of derivatives was obtained and the cellular photocytotoxicity was evaluated invitro against three different human tumor cell lines with EC50 (0.08–4.96μM) values reaching the nanomolar level. Selected compounds were investigated by laser flash photolysis. The most photocytotoxic derivative, exhibiting a fairly long-lived triplet state (τ ∼ 7μs) and absorbance in the UV–Vis, was tested in the photo-oxidations of 9,10-anthracenedipropionic acid (ADPA) by singlet oxygen. The photosentizing properties are responsible for the compounds’ ability to photoinduce massive cell death with involvement of mitochondria.

A ditalini pasta with a mixture of durum wheat and beta-glucan enriched barley flour (BF) (60/40%, w/w) was found to have a final content of 5% beta-glucan (BF-ditalini). Main quality parameters of BF-ditalini, water uptake and starch-protein texture, were comparable with those of 100% durum wheat ditalini (control). After in vitro simulated intestinal digestion, the content of beta-glucan in the post intestinal (PI) supernatant of BF-ditalini processed with its cooking water (soup) was six fold higher than that of pasta asciutta. BF-ditalini soup, but not pasta asciutta, strongly delayed the hydrolysis of the starch, without difference of viscosity between PI supernatant and control. PI supernatant from BF-ditalini showed total phenol content and antioxidant capacity significantly higher (p < 0.001) than control. In conclusion, ditalini pasta fortified with 40% BF may be considered a dietary product with high quality indexes and of functional interest for the abundance of antioxidant phenols, and for the hypoglicemic effect of beta-glucan when ingested as a soup. (C) 2016 Elsevier Ltd. All rights reserved

Derivatives of the new ring system 1,4-dihydropyrazolo[4,3-c][1,2,6] benzothiadiazocin-11(10H)one 5,5-dioxide were synthesized in five or six steps in 57-66% overall yields and tested as COX inhibitors.

Despite improvements in the treatment and prevention of cancer, the number of new diagnoses continues to rise; this has fuelled substantial interest in the development of new and effective chemotherapeutic agents. Compounds of the triazene class, such as dacarbazine, have been used in the clinical management of many cancer types including brain, leukemia, and melanoma. A new compound class bearing a triazenoazaindole scaffold was synthesized with the aim of identifying new antiproliferative agents. Compounds 5 a-g and 6 a-c were screened against a panel of human tumor cell lines, and two of them, 5 e and 5 f, showed cytotoxicity (GI(50) range: 2.2-8.2 μM) in all cell lines. These two compounds even maintained their cytotoxicity in some multidrug-resistant cell lines. Flow cytometry analysis demonstrated their ability to induce cell death by apoptosis with involvement of lysosomes.

A new series of pyrazolo[3,4-h]quinolines, heteroanalogues of angelicin was conveniently prepared with a broad substitution pattern. A large number of derivatives was obtained and the cellular photocytotoxicity was evaluated in vitro against 5 different human tumor cell lines with GI50 values reaching the nanomolar level (14.52e0.04 mM). Selected compounds were able to photoinduce a massive cell death with the involvement of mitochondria. Their photodamage cellular targets were proteins and lipids and they did not cause any kind of DNA photodamage. This latter event is of considerable importance in the modulation of long term side effects, generally associated with the use of classical furocoumarins.

A new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and the indole unit bound to position 2 of the thiazole ring was substituted by a 7-azaindole moiety, was efficiently synthesized. Two of the new nortopsentin analogues showed good antiproliferative effect against the totality of the NCI full panel of human tumor cell lines (~60) having GI50 values ranging from low micromolar to nanomolar level. The mechanism of the antiproliferative effect of these derivatives, investigated on human hepatoma HepG2 cells, was pro-apoptotic, being associated with externalization of plasma membrane phosphatidylserine and mitochondrial dysfunction. Moreover, the compounds induced a concentration-dependent accumulation of cells in the subG0/G1phase, while confined viable cells in G2/M phase.

Water-soluble isoindoloquinoxalin (IIQ) imines and the corresponding acetates were conveniently prepared from the key intermediates 2-(2′-aminophenyl)-2H-isoindole-1-carbonitriles obtained by a Strecker reaction between substituted 1,2-dicarbaldehydes and 1,2-phenylenediamines. Both series were screened by the National Cancer Institute (Bethesda, MD) and showed potent antiproliferative activity against a panel of 60 human tumor cell lines. Several of the novel compounds showed GI50 values at a nanomolar level on the majority of the tested cell lines. Among IIQ derivatives, methoxy substituents at positions 3 and 8 or/and 9 were especially effective in impairing cell cycle progression and inducing apoptosis in cancer cells. These effects were associated to IIQ-mediated impairment of tubulin polymerization at pharmacologically significant concentrations of tested compounds. In addition, impaired DNA topoisomerase I functions and perturbation in telomere architecture were observed in cells exposed to micromolar concentrations of IIQ derivatives. The above results suggest that IIQ derivatives exhibit multi-target cytotoxic activities.

Two new series of nortopsentin analogues, in which the imidazole ring of the natural product was replaced by thiazole and indole units were both substituted by 7-azaindole moieties or one indole unit was replaced by a 6-azaindole portion, were efficiently synthesized. Compounds belonging to both series inhibited the growth of HCT-116 colorectal cancer cells at low micromolar concentrations, whereas they did not affect the viability of normal-like intestinal cells. A compound of the former series induced apoptosis, evident as externalization of plasma membrane phosphatidylserine (PS), and changes of mitochondrial trans-membrane potential, while blocking the cell cycle in G2/M phase. In contrast, a derivative of the latter series elicited distinct responses in accordance with the dose. Thus, low concentrations (GI30) induced morphological changes characteristic of autophagic death with massive formation of cytoplasmic acid vacuoles without apparent loss of nuclear material, and with arrest of cell cycle at the G1 phase, whereas higher concentrations (GI70) induced apoptosis with arrest of cell cycle at the G1 phase. © 2015 by the authors licensee MDPI Basel Switzerland.

A new series of pyrrolo[3,4- h ]quinazolines was conveniently prepared with a broad substitution pattern. A large number of derivatives was obtained and the cellular cytotoxicity was evaluated in vitro against 5 different human tumor cell lines with GI 50 values reaching the low micromolar level (1.3–19.8 μM). These compounds were able to induce cell death mainly by apoptosis through a mitochondrial dependent pathway. Selected compounds showed antimitotic activity and a reduction of tubulin polymerization in a concentration-dependent manner. Moreover, they showed anti-angiogenic properties since reduced in vitro endothelial cell migration and disrupted HUVEC capillary-like tube network in Matrigel.

A large number of indolyl-4-azaindolyl thiazoles, nortopsentin analogues, were conveniently synthesized. The antiproliferative activity of the new derivatives was examined against four human tumor cell lines with different histologic origin. Seven derivatives consistently reduced the growth of the experimental models independently of TP53 gene status and exhibited the highest activity against the malignant peritoneal mesothelioma (STO) cell line. The most active compound of this series acts as a CDK1 inhibitor, and was found to cause cell cycle arrest at G 2 /M phase, to induce apoptosis by preventing the phosphorylation of survivin in Thr 34 and to increase the cytotoxic activity of paclitaxel in STO cells.

Derivatives of new ring systems 11H-pyrido[3',2':4,5]pyrrolo[3,2-c]cinnoline and pyrido[3',2':4,5]pyrrolo[1,2-c][1,2,3]benzotriazine have been prepared from the key intermediates 2-(1H-pyrrolo[2,3-b]pyridin-2-yl)anilines in excellent yields (94-99%) and screened by the National Cancer Institute (Bethesda, MD) on about 60 human tumor cell lines derived from nine cancer cell types. The tested compounds exhibited antiproliferative activity against all the human cell lines, showing comparable MG_MID (mean graph midpoint) values in the range of 0.74-1.15 μM. A particular efficacy was observed against the leukemia subpanel (GI50 = 0.73-0.0090 μM). Flow cytometric analysis of the cell cycle demonstrated an increase in the percentage of cells in the G2/M phase. The compounds caused apoptosis of the cells, mitochondrial depolarization, generation of reactive oxygen species, and activation of caspase-3, caspase-8, and caspase-9. Moreover, they acted as topoisomerase I inhibitors.

‘Interrupted’ diazotization of 3-aminoindoles and 3-aminopyrroles, achieved by quenching with cold water immediately after the addition of nitrite, led, in good yields, to stable compounds whose structures were identified to be the diazonium species with nitrate as the counter ion, which show no saline character.