Total synthesis of tetracyclic kynurenic acid analogues isolated from chestnut honey

A short and efficient synthesis of novel tetracyclic Kynurenic acid analogues, isolated from chestnut honey, is described. The crucial step of the strategy was a MW-assisted cyclization of enamines of ethyl dioxohexahydropyrrolizine and 2,3-dioxooctahydroindolizine carboxylates to obtain 2,3,6,11b-tetrahydro-1H-pyrrolizino[2,1-b]quinoline-5,11-dione and 5,8,91,011,11a-hexahydroindolizino[2,1-b]quinoline-6,12-dione, respectively. Because of its modular nature, the synthetic strategy can have value as a general method for the preparation of compounds containing these new heterocyclic scaffolds

4-Quinolone fused heterocyclic ring systems by intramolecular reactions of 4-quinolone-2-carboxamides

A versatile synthetic route to new 4-quinolone-based polycyclic systems is described. TFA-catalyzed intramolecular reaction of N-unsubstituted quinolone-2-carboxylic acid amides gives structurally diverse compounds, depending on the length of the chain. Acid treatment of \u3b2-oxoamides furnishes 3H-pyrazino[1,2-a]quinoline-4,6-diones, due to the nucleophilic attack of N-1 to the carbonyl group, whereas TFA treatment of \u3b4- and \u3b5-oxoamides leads to the formation of tetracyclic compounds by a tandem heteroannulation reaction

COVID-19 infection and rheumatoid arthritis: Faraway, so close!

The outbreak of the new coronavirus infections COVID-19 in December 2019 in China has quickly become a global health emergency. Given the lack of specific anti-viral therapies, the current management of severe acute respiratory syndrome coronaviruses (SARS-CoV-2) is mainly supportive, even though several compounds are now under investigation for the treatment of this life-threatening disease. COVID-19 pandemic is certainly conditioning the treatment strategy of a complex disorder as rheumatoid arthritis (RA), whose infectious risk is increased compared to the general population because of an overall impairment of immune system typical of autoimmune diseases combined with the iatrogenic effect generated by corticosteroids and immunosuppressive drugs. However, the increasing knowledge about the pathophysiology of SARS-CoV-2 infection is leading to consider some anti-rheumatic drugs as potential treatment options for the management of COVID-19. In this review we will critically analyse the evidences on either positive or negative effect of drugs commonly used to treat RA in this particular scenario, in order to optimize the current approach to RA patients

Intramolecular friedel-crafts reaction of indoles with carbonyl groups: a simple synthesis of 3- and 4-substituted \u3b2-carbolin-1-ones

The intramolecular Friedel-Crafts reaction of indole-2-carboxylic acid \u3b2-oxoamides catalyzed by trifluoroacetic acid or InCl3, is a convenient method for the synthesis of 3-aryl-, 4-aryl-, and 4-alkyl-\u3b2-carbolin-1-ones

Growth inhibition of human ovarian carcinoma by a novel AvidinOX-anchored biotinylated camptothecin derivative

Oxidized form of avidin, named AvidinOX, provides stable fixation of biotinylated molecules in tissues thus representing a breakthrough in topical treatment of cancer. AvidinOX proved to be a stable receptor for radiolabeled biotin, biotinylated antibodies and cells. In order to expand applicability of the AvidinOX-based delivery platform, in the present study we investigated the possibility to hold biotinylated chemotherapeutics in AvidinOX-treated sites. A novel biotinylated gimatecan-derived camptothecin, coded ST8161AA1, was injected at suboptimal doses into human tumors xenografted in mice alone or pre-complexed to AvidinOX. Significantly higher growth inhibition was observed when the drug was anchored to AvidinOX suggesting the potential utility of this delivery modality for the local treatment of inoperable tumors

Influence of the adamantyl moiety on the activity of biphenylacrylohydroxamic acid-based HDAC inhibitors

To investigate the influence of the adamantyl group on the biological properties of known HDAC inhibitors with a 4-phenylcinnamic skeleton, a series of compounds having the adamantyl moiety in the cap structure were synthesized and compared to the corresponding hydroxamic acids lacking this group. An unexpected finding was the substantial reduction of inhibitory activity toward the tested enzymes, in particular HDAC6, following the introduction of the adamantyl group. In spite of the reduced ability to function as HDAC inhibitors, the compounds containing the adamantyl moiety still retained a good efficacy as antiproliferative and proapoptotic agents. A selected compound (2c; ST3056) of this series exhibited an appreciable antitumor activity against the colon carcinoma xenograft HCT116

Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors

Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC50values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability

Design, modeling, synthesis and biological activity evaluation of camptothecin linked platinum anticancer agents

The design, modeling, synthesis and biological activity evaluation of two hybrid agents formed by 7-oxyiminomethylcamptothecin derivatives and diaminedichloro-platinum (II) complex are reported. The compounds showed growth inhibitory activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. The derivatives were active in all the tested cell lines, and compound 1b, the most active one, was able to overcome cisplatin resistance in the osteosarcoma U2OS/Pt cell line. Platinum-containing camptothecins produced platinum-DNA adducts and topoisomerase I-mediated DNA damage with cleavage pattern and persistence similar to SN38, the active principle of irinotecan. Compound 1b exhibited an appreciable antitumor activity in vivo against human H460 tumor xenograft, comparable to that of irinotecan at lower well-tolerated dose levels and superior to cisplatin. The results support the interpretation that the diaminedichloro-platinum (II) complex conjugated via an oxyiminomethyl linker at the 7-position of the camptothecin resulted in a new class of effective antitumor compounds

Investigation on the ZBG-functionality of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase inhibitors

A series of alternative Zn-binding groups were explored in the design of phenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors. Most of the synthesized compounds were less effective than the parent hydroxamic acid. However, the profile of activity shown by the analog bearing a hydroxyurea head group, makes this derivative promising for further investigation

7-Azaindole-1-carboxamides as a new class of PARP-1 inhibitors

7-Azaindole-1-carboxamides were designed as a new class of PARP-1 inhibitors. The compounds displayed a variable pattern of target inhibition profile that, in part, paralleled the antiproliferative activity in cell lines characterized by homologous recombination defects. A selected compound (1l; ST7710AA1) showed significant in vitro target inhibition and capability to substantially bypass the multidrug resistance mediated by Pgp. In antitumor activity studies against the MX1 human breast carcinoma growth in nude mice, the compound exhibited an effect similar to that of Olaparib in terms of tumor volume inhibition when used at a lower dose than the reference compound. Treatment was well tolerated, as no deaths or significant weight losses were observed among the treated animals