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The correction of protein folding is fundamental for cellular functionality and its failure can lead to severe diseases. In this context, molecular chaperones are crucial players involved in the tricky process of assisting in protein folding, stabilization, and degradation. Chaperones, such as heat shock proteins (HSP) 90, 70, and 60, operate within complex systems, interacting with co-chaperones both to prevent protein misfolding and direct to the correct folding. Chaperone targeting drugs could represent a challenging approach for the treatment of cystic fibrosis (CF), an autosomal recessive genetic disease caused by mutations in the CFTR gene, encoding for the CFTR chloride channel. In this review, we discuss the potential role of molecular chaperones as proteostasis modulators affecting CFTR biogenesis. In particular, we focused on HSP90 and HSP70, for their key role in CFTR folding and trafficking, as well as on HSP60 for its involvement in the inflammation process., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Although substantial advances have been obtained in the pharmacological treatment of cystic fibrosis (CF) with the approval of Kaftrio, a combination of two correctors (VX-661, VX-445) and one potentiator (VX-770), new modulators are still needed to rescue F508del and other CFTR mutants with trafficking defects. We have previously identified PP compounds based on a tricyclic core as correctors with high efficacy in the rescue of F508del-CFTR on native epithelial cells of CF patients, particularly in combination with class 1 correctors (VX-809, VX-661). Compound PP028 was found as a lead candidate for the high rescue of F508del-CFTR and used for mechanistic insight indicating that PP028 behaves as a class 3 corrector, similarly to VX-445. From the exploration of the chemical space around the hit structure, based on iterative cycles of chemical synthesis and functional testing, the class of 6,9-dihydro-5H-pyrrolo [3,2-h]quinazolines with corrector activity was discovered. Within a series of 38 analogues, two derivatives emerged as promising candidates and used for further insight to assess the mechanism of action. Both compounds, decorated with a benzensulfonylamino group at the pyrimidine moiety, were able to generate a dose-dependent increase in CFTR function, particularly in the presence of VX-809. Half-effective concentrations (EC 50 ) were in the single digit micromolar range and decreased in the presence of VX-809 thus indicating a synergistic interaction with class 1 correctors. Synergy was also observed with corr-4a (class 2 corrector) but not with VX-445 and PP028 (class 3 correctors) indicating that the new compounds behave as class 3 correctors. These results suggest that tricyclic pyrrolo-quinazolines interact with CFTR at a site different from that of VX-809 and represent a novel class of CFTR correctors suitable for combinatorial pharmacological treatments for the basic defect in CF., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:PAOLA BARRAJA reports financial support was provided by Italian Cystic Fibrosis Research Foundation. PAOLA BARRAJA, VIRGINIA SPANO’, L. J. V. GALIETTA has patent pending to WO 2020104558 A1 20200528. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Unsatisfactory outcomes for relapsed/refractory lymphoma patients prompt continuing efforts to develop new therapeutic strategies. Our previous studies on pyrrole-based anti-lymphoma agents led us to synthesize a new series of twenty-six pyrrolo[3',4':3,4]cyclohepta[1,2-d] [1,2]oxazole derivatives and study their antiproliferative effects against a panel of four non-Hodgkin lymphoma cell lines. Several candidates showed significant anti-proliferative effects, with IC 50 's reaching the sub-micromolar range in at least one cell line, with compound 3z demonstrating sub-micromolar growth inhibitory effects towards the entire panel. The VL51 cell line was the most sensitive, with an IC 50 value of 0.10 μM for 3z. Our earlier studies had shown that tubulin was a prominent target of many of our oxazole derivatives. We therefore examined their effects on tubulin assembly and colchicine binding. While 3u and 3z did not appear to target tubulin, good activity was observed with 3d and 3p. Molecular docking and molecular dynamics simulations allowed us to rationalize the binding mode of the synthesized compounds toward tubulin. All ligands exhibited a better affinity for the colchicine site, confirming their specificity for this binding pocket. In particular, a better affinity and free energy of binding was observed for 3d and 3p. This result was confirmed by experimental data, indicating that, although both 3d and 3p significantly affected tubulin assembly, only 3d showed activity comparable to that of combretastatin A-4, while 3p was about 4-fold less active. Cell cycle analysis showed that compounds 3u and especially 3z induced a block in G2/M, a strong decrease in S phase even at low compound concentrations and apoptosis through the mitochondrial pathway. Thus, the mechanism of action of 3u and 3z remains to be elucidated. Very high selectivity toward cancer cells and low toxicity in human peripheral blood lymphocytes were observed, highlighting the good potential of these agents in cancer therapy and encouraging further exploration of this compound class to obtain new small molecules as effective lymphoma treatments., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Francesco Bertoni reports financial support was provided by ADC Therapeutics, Bayer AG, Cellestia, Helsinn, HTG Molecular Diagnostics, ImmunoGen, Menarini Ricerche, NEOMED Therapeutics 1, Nordic Nanovector ASA, Helsinn, Menarini. Eugenio Gaudio reports a relationship with Helsinn Healthcare SA that includes: employment., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Pyrrolomycins (PMs) are a family of naturally occurring antibiotic agents, isolated from the fermentation broth of Actinosporangium and Streptomyces species. Pursuing our studies on pyrrolomycins, we performed the total synthesis of the F-series pyrrolomycins (1-4) by microwave-assisted synthesis (MAOS), thus obtaining the title compounds in excellent yields (63-69%). Considering that there is no evidence so far of the anticancer effect of this class of compounds, we investigated PMs for their antiproliferative activity against HCT116 and MCF-7 cancer cell lines. PMs showed anticancer activity at submicromolar level with a minimal effect on normal epithelial cell line (hTERT RPE-1), and they were able to induce several morphological changes including elongated cells, cytoplasm vacuolization, long and thin filopodia as well as the appearance of tunneling nanotubes (TNTs). These data suggest that PMs could act by impairing the cell membranes and the cytoskeleton organization, with subsequent increase of ROS generation and the activation of different forms of non-apoptotic cell death., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Viruses have been recognized as the etiological agents responsible for many pathological conditions ranging from asymptomatic infections to serious diseases, even leading to death. For this reason, many efforts have been made to identify selective viral targets with the aim of developing efficient therapeutic strategies, devoid of drug-resistance issues. Considering their crucial role in the viral life cycle, polymerases are very attractive targets. Among the classes of compounds explored as viral polymerases inhibitors, here we present an overview of non-nucleoside triazole-based compounds identified in the last fifteen years. Furthermore, the structure-activity relationships (SAR) of the different chemical entities are described in order to highlight the key chemical features required for the development of effective antiviral agents., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Isabella Romeo reports financial support was provided by Calabria Region., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Lymphomas are among the ten most common cancers, and, although progress has been achieved in increasing survival, there is still an unmet need for more effective therapeutic approaches, including better options for patients with refractory tumors that initially respond but then relapse. The lack of effective alternative treatment options highlights the need to develop new therapeutic strategies capable of improving survival prospects for lymphoma patients. Herein, we describe the identification and exploration of the SAR of a series of [1,2]oxazolo[5,4-e]isoindoles as potent small molecules that bind to the colchicine site of tubulin and that have promise for the treatment of refractory lymphomas. Exploration of the chemical space of this class of compounds at the pyrrole moiety and at the [1,2]oxazole ring highlighted two compounds bearing a 3,5-dimethoxybenzyl and a 3,4,5-trimethoxybenzyl group as potent candidates and showed that structural modifications at the isoxazole moiety are generally not favorable for activity. The two best candidates showed efficacy against different lymphoma histotypes and displayed 88 and 80% inhibition of colchicine binding fitting well into the colchicine pocket, as demonstrated by X-ray crystallography T 2 R-TTL-complexes, docking and thermodynamic analysis of the tubulin-colchicine complex structure. These results were confirmed by transcriptome data, thus indicating [1,2]oxazolo[5,4-e]isoindoles are promising candidates as antitubulin agents for the treatment of refractory lymphomas., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Searching for new small molecules as photosensitizing agents, we have developed a class of twenty-five pyrimido[5,4-g]indolizine and pyrimido[4,5-c]pyrrolo[1,2-a]azepines with a good substitution pattern defining a versatile synthetic pathway to approach the title ring system. All compounds were evaluated for their photocytotoxicity on a triple negative human breast cancer cell line (MDA-MB-231) in the dark and under UVA light (2.0 J/cm 2 ). The most effective compounds exhibited a photoantiproliferative activity with IC 50 values up to nanomolar ranges. Interestingly, these new developed compounds showed high selectivity towards cancerous cells with respect to non-cancerous ones. Moreover, four representative derivatives demonstrated to be phototoxic also against an additional human HER2 positive breast cancer cell line (HCC1954), and against the HER2 positive vesical cancer cell line (T24) harboring Hras mutation. Mechanistic studies performed in triple negative MDA-MB-231 cancer cells revealed the ability of the compounds to increase reactive oxygen species (ROS) production and to induce a thiol redox stress, thus triggering cancer cell death through apoptosis. Apoptotic cell death was also induced in highly aggressive and metastatic HER2 positive Hras mutated T24-treated bladder cancer cells. Overall, our data confirm that these new small photosensitizing agents may represent very promising candidates for phototherapy application against highly aggressive and resistant cancers., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Despite progressive advances in understanding the molecular biology of acute myeloid leukemia (AML), the conventional therapeutic approach has not changed substantially, and the outcome for most patients is poor. Thus, continuous efforts on the discovery of new compounds with improved features are required. Following a multistep sequence, we have identified a new tetracyclic ring system with strong antiproliferative activity towards several haematological cell lines. The new compounds possess structural properties typical of inactive-state-binding kinase inhibitors and are structurally related to quizartinib which is known as type-II tyrosine kinase inhibitor. In particular, the high activity found in two cell lines MOLM-13 and MV4-11, expressing the constitutively activated mutant FLT3/ITD, indicates inhibition of FLT3 kinase and on the basis of structure-activity relationship (SAR) the presence of an ureido moiety demonstrates to play a key role in driving the antiproliferative activity towards these cell lines. Molecular modelling studies supported the mechanism of recognition of the most active compounds within the FLT3 pocket where quizartinib binds. Moreover, Molecular Dynamics simulation (MDs) revealed the formation of a recurrent H-bond with Asp829, which more stabilizes the complex of 9c and the FLT3 inactive state. In MV4-11 cell line compound 9c reduces the phosphorylation of FLT3 (Y591) and some of its downstream targets leading to cell cycle arrest at G1 phase and induction of apoptosis. In an MV4-11 xenograft mouse model, 9c significantly reduces the tumor growth at the dose of 1-3 mg/kg without apparent toxicity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interest Roberto Ronca reports financial support was provided by Italian Association for Cancer Research. CILIBRASI V., SPANO’ V., MONTALBANO A., BARRAJA P. has patent NEW THERAPEUTIC AGENTS FOR THE TREATMENT OF HAEMATOLOGICAL PATHOLOGIES issued to University of Palermo., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

A series of [1,3]thiazolo[4,5-e]isoindoles has been synthesized through a versatile and high yielding multistep sequence. Evaluation of the antiproliferative activity of the new compounds on the full NCI human tumor cell line panel highlighted several compounds that are able to inhibit tumor cell proliferation at micromolar-submicromolar concentrations. The most active derivative 11g was found to cause cell cycle arrest at the G2/M phase and induce apoptosis in HeLa cells, following the mitochondrial pathway, making it a lead compound for the discovery of new antimitotic drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The discovery of novel synthetic compounds with drug-like properties is an ongoing challenge in medicinal chemistry. Natural products have inspired the synthesis of compounds for pharmaceutical application, most of which are based on N-heterocyclic motifs. Among these, the pyrrole ring is one of the most explored heterocycles in drug discovery programs for several therapeutic areas, confirmed by the high number of pyrrole-based drugs reaching the market. In the present review, we focused on pyrrole and its hetero-fused derivatives with anticancer, antimicrobial, and antiviral activities, reported in the literature between 2015 and 2019, for which a specific target was identified, being responsible for their biological activity. It emerges that the powerful pharmaceutical and pharmacological features provided by the pyrrole nucleus as pharmacophore unit of many drugs are still recognized by medicinal chemists., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Cystic fibrosis (CF) is a genetic disorder produced by the loss of function of CFTR, a main chloride channel involved in transepithelial salt and water transport. CFTR function can be rescued by small molecules called "potentiators" which increase gating activity of CFTR on epithelial surfaces. High throughput screening (HTS) assays allowed the identification of new chemical entities endowed with potentiator properties, further improved through medicinal chemistry optimization. In this review, the most relevant classes of CFTR potentiators developed in the last decade were explored, focusing on structure-activity relationships (SAR) of the different chemical entities, as a useful tool for the improvement of their pharmacological activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Multi-target molecular entities, offer a path to progress both in understanding causes of disease and in defining effective small molecule treatments. Coumarin and its derivatives belong to an important group of natural compounds with diverse biological properties. They are found in vegetables and plants for which literature reports thousands of publications for the great variety of biological applications among which the photoprotective effects, thus being considered multi-targeting agents. Their furan condensed analogues constitute the family of furocoumarins, less represented in the literature, endowed with photosensitizing properties and often used for the treatment of skin diseases such as vitiligo and psoriasis. Despite the study of biological properties of linear and angular furocumarins dates back to ancient times, mainly as photosensitizers, these small molecules still represent an attractive scaffold for further development and applications in several therapeutic fields. The aim of the present review is to summarize the most promising chemical entities belonging to the class of furocumarins and coumarins, emerged in the last decades, and the methods used for their synthesis with a particular focus on main targets involved in the cystic fibrosis treatment., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Deletion of phenylalanine at position 508 (F508del) in the CFTR protein, is the most common mutation causing cystic fibrosis (CF). F508del causes misfolding and rapid degradation of CFTR protein a defect that can be targeted with pharmacological agents termed "correctors". Correctors belong to various chemical classes but are generally small molecules based on nitrogen sulfur or oxygen heterocycles. The mechanism of action of correctors is generally unknown but there is experimental evidence that some of them can directly act on mutant CFTR improving folding and stability. Here we overview the characteristics of the various F508del correctors described so far to obtain indications on key chemical structures and modifications that are required for mutant protein rescue., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Multiple myeloma (MM) is still an incurable hematologic malignancy. Although new therapeutic strategies have been developed to target different pathways in malignant cells, such as proliferation, differentiation, and apoptosis, better survival rates have also been achieved by the introduction of autologous stem cell transplantation (ASCT). Hematopoietic stem cell transplantation and novel targeted agents, such as proteasome inhibitors, monoclonal antibodies, immunomodulatory drugs, check-point inhibitors and epigenetic modulators, have significantly achieved long remission time and increased survival rates. However, most patients relapse, develop resistance, and eventually die because of refractory disease. All these issues highlight the need to investigate newer therapeutic targets to improve patient outcomes. Natural products play an important role in anti-tumor drug discovery, for this reason, in the investigation of novel natural anti-MM agents, we focused on natural polyphenols. Moreover, plant extracts show no or low toxicity towards normal cells and some of them have also a favorable pharmacokinetic profile. The biological activities of plant extracts are mainly due to their content in polyphenols, flavonoids, and terpenoids. Numerous studies showed that polyphenols, generally recognized as antioxidants, possess anticancer and pro-apoptosis properties. Other studies reported the potential clinical applications of flavonoids for their well-known protective and therapeutic effects against cancer, cardiovascular, and neurodegenerative diseases. The combination of plant extracts with anti-cancer drugs may offer a relevant advantage for therapeutic efficacy by sensitizing malignant cells to drugs and overcoming drug-induced resistance in cancer. For all these reasons, a significant number of polyphenolic compounds isolated from plants are still used nowadays in cancer clinical practice in combination with other drugs, also against hematologic malignancies., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

[1,2,3]Triazolo[4,5-h][1,6]naphthyridines and [1,3]oxazolo[5,4-h][1,6]naphthyridines were synthesized with the aim to investigate their photocytotoxic activity. Upon irradiation, oxazolo-naphtapyridines induced light-dependent cell death at nanomolar/low micromolar concentrations (EC 50 0.01-6.59 μM). The most photocytotoxic derivative showed very high selectivity and photocytotoxicity indexes (SI = 72-86, PTI>5000), along with a triplet excited state with exceptionally long lifetime (18.0 μs) and high molar absorptivity (29781 ± 180 M -1 cm -1 at λ max 315 nm). The light-induced production of ROS promptly induced an unquenchable apoptotic process selectively in tumor cells, with mitochondrial and lysosomal involvement. Altogether, these results demonstrate that the most active compound acts as a promising singlet oxygen sensitizer for biological applications., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Pyrrolizinones represent an interesting class of compounds with varied degrees of structural complexity and pharmacological activity. Among these, 9H-pyrido[2,3-b]pyrrolizin-9-one, tripentone analogs, recently reported by us, showed significant antiproliferative activity against human tumor cell lines, inducing apoptosis and not affecting viability of Caco-2 differentiated in normal intestinal-like cells. Considering their interesting biological activity, their 5H-pyrido[3,2-b]pyrrolizin-5-one analogs were efficiently synthesized in good to excellent yields (61-91%). All tripentone derivatives were tested to assess their cytotoxicity against two human tumor cell lines, HCT-116 (human colorectal carcinoma) and MCF-7 (human breast cancer). The most active derivatives, with IC 50 ranging from 0.11 to 16.11 μM, did not affect viability of Caco-2 differentiated in normal intestinal-like cells, suggesting tumor cells as the main target of their cytotoxic action. The same compounds, further investigated, showed that they did not exert necrotic effects, while induced a clear shift of viable cells towards early apoptosis confining the cells in the mitotic phases., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

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 EC 50 values reaching the submicromolar level. The mechanism of action was evaluated., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

A series of [1,2]Oxazolo [5,4-e]isoindoles has been synthesized through a versatile and high yielding sequence. All the new structures showed in the 1 HNMR spectra, the typical signal in the 8.34-8.47 ppm attributable to the H-3 of the [1,2]oxazole moiety. Among all derivatives, methoxy benzyl substituents at positions 3 and 4 or/and 5 were very effective in reducing the growth of different tumor cell lines, including diffuse malignant peritoneal mesothelioma (DMPM), an uncommon and rapidly malignancy poorly responsive to available therapeutic options. The most active compound 6j was found to impair tubulin polymerization, cause cell cycle arrest at G2/M phase and induce apoptosis in DMPM cells, making it as a new lead for the discovery of new potent antimitotic drugs., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

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 in vitro against three different human tumor cell lines with EC50 (0.08-4.96 μM) 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 ∼ 7 μs) 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., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

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 (14.52-0.04 μM). 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., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Three new ring systems, pyrido[2',3':3,4]pyrrolo[1,2-a]quinoxalines, pyrido[3',2':3,4]pyrrolo[1,2-a]quinoxalines and pyrido[2',3':5,6]pyrazino[2,1-a]isoindoles, were synthesized through an aza-substitution on the already active isoindolo-quinoxaline system and in particular in the position 7 or 4 of the isoindole moiety and in position 5 of the quinoxaline portion. All new compounds were screened by the National Cancer Institute (Bethesda, MD) against a panel of 60 human tumor cell lines. Biological results of the most active derivatives, with pGI50 values between 7.09 and 7.27, confirmed the importance of the presence of methoxy substituents for biological activity. The anti-proliferative effect of selected quinoxalines was associated with apoptosis of the cells and arrest in G2/M phase of the cell cycle. DNA binding properties of the compounds was also assessed to investigate the possible mechanism of action., (Copyright © 2015. Published by Elsevier Masson SAS.)

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 GI₅₀ 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., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Pyrrolo[2,1-c][1,2,4]triazines 4a-g were directly obtained from the reaction of 2-diazopyrroles 1a and b with the sodium salts of beta-diketones, beta-carbonitriles, and beta-dinitriles. Only when the 2-diazopyrroles were coupled with ethyl cyanoacetate, it was possible to isolate, together with the pyrrolotriazines, the intermediate hydrazones 3 which, in turn, cyclised to the title ring system. Pyrrolotriazines 4a-e were evaluated for cytotoxic activity against a panel of 60 human cancer cell lines by the National Cancer Institute and some of them demonstrated inhibitory effects in the growth of a wide range of cancer cell lines generally at 10(-5) M level and in some cases at micromolar concentrations.

The pyrrolo[1,2-f]phenanthridines 8-22 and the corresponding non-rigid analogues 23-41 were synthesised and their ability to inhibit the replication of HIV-1 was tested. Only the polycyclic derivatives 10, 11, and 13 showed a weak anti-HIV activity, whereas several pyrrolo-phenanthridines (8, 10, 16-18) were found to stimulate the multiplication of MT-4 cells at low concentrations. Derivative 10 demonstrated to possess the unique property of stimulating the multiplication of lymphocytes joined to HIV inhibition.