Microwave Assisted Synthesis of Pyridophenoxazinones, a Class of Powerful Antiproliferative Compounds

In order to obtain new antiproliferative compounds good for acting through the forementioned mechanisms, including DNA intercalation and topoisomerase inhibition, our attention was focused on the derivatives of pyridophenoxazinone (PPH, 1 R=H) system, an iminoquinone containing a planar tetracyclic system suitable for intercalating DNA G-C base pairs in a site specific mode(2). Namely, we designed, after molecular modeling calculations, PPH carboxyamide derivatives holding at C-9 and C-10 positions an amino acidic chain or a sugar. Unfortunately, the real obstacle to the availability of such molecule was represented by their synthesis. Therefore, in our opinion it seems to be worthwhile to report a new microwave (μW) assisted synthetic procedure to prepare PPH carboxyamides. In order to assess the validity of our method, we applied the procedure to the synthesis of variously substituted PPHs 1 and received evidence that microwave irradiation enables the preparation of those compounds in high yields and short reaction times

Stereoselective Synthesis of Selenium-Containing Glycoconjugates via the Mitsunobu Reaction

A simple and efficient route for the synthesis of new glycoconjugates has been developed.The approach acts as a model for a mini-library of compounds with a deoxy-selenosugar core joinedto a polyphenolic moiety with well-known antioxidant properties. An unexpected stereocontroldetected in the Mitsunobu key reaction led to the most attractive product showing a natural Dconfiguration. Thus, we were able to obtain the target molecules from the commercially availableD-ribose via a shorter and convenient sequence of reaction

Antitumor Agents. 5. Synthesis, Structure-Activity Relationships, and Biological Evaluation of Dimethyl-5H-pyridophenoxazin-5-ones, Tetrahydro-5H-benzopyridophenoxazin-5-ones, and 5H-Benzopyridophenoxazin-5-ones with Potent Antiproliferative Activity

New antiproliferative compounds, dimethyl-5H-pyrido[3,2-a]phenoxazin-5-ones (1-6), tetrahydro-5Hbenzopyrido[ 2,3-j]phenoxazin-5-ones (7-9), and 5H-benzopyrido[3,2-a]phenoxazin-5-ones (10-12) were synthesized and evaluated against representative human neoplastic cell lines. Dimethyl derivatives 1-6 were more active against carcinoma than leukemia cell lines. The tetrahydrobenzo derivatives 7-9 were scarcely active, whereas the corresponding benzo derivatives 10-12 showed notable cytotoxicity against a majority of the tested cell lines. Molecular modeling studies indicated that the high potency of 10 and 11, the most cytotoxic compounds of the whole series, could be due to the position of the condensed benzene ring, which favors ð-ð stacking interactions with purine and pyrimidine bases in the DNA active site. Biological studies suggested that 10-12 have no effect on human topoisomerases I and II and that they induce arrest at the G2/M phase

Antitumor Agents 6. Synthesis, Structure-Activity Relationships, and Biological Evaluation of Spiro[imidazolidine-4,3′-thieno[2,3-g]quinoline]-tetraones and Spiro[thieno[2,3-g]quinoline-3,5′- [1,2,4]triazinane]-tetraones with Potent Antiproliferative Activity†

Two series of quinolinquinone derivatives, 2′H-spiro[imidazolidine-4,3′-thieno[2,3-g]quinoline]-2,4′,5,9′- tetraones (2a-n) and 2H-spiro[thieno[2,3-g]quinoline-3,5′-[1,2,4]triazinane]-3′,4,6′,9-tetraones (3a-e), were designed and synthesized using the previously described ethyl 3-amino-4,9-dioxo-2,3,4,9-tetrahydrothieno[2,3- g]quinoline-3-carboxylate (1) as a starting material. All compounds were evaluated for their antiproliferative activity against a panel of representative liquid and solid human tumor cell lines and exhibit IC50 values in the micromolar/submicromolar range. Series 2 displayed higher cytotoxicity than did series 3. The nature of the substituents on both imidazoline and triazinane N1 nitrogen markedly affected the activity profile of these series. Spectrophotometric and fluorescence measurements as well as unwinding assays performed on the most cytotoxic compounds, 2c, 2g, and 2k, showed that they are nonintercalative DNA agents and inhibit the catalytic activity of Topo II in a concentration-dependent mode. 2g was the most active Topo II inhibitor with activity levels comparable to those of VP-16

New Seleno-Glyconjugates for Nutraceutical Application

Oxidative stress is a disequilibrium redox condition that occurs due to high concentration of prooxidant reactive species (RS) and, by comparison, a lower concentration of endogenous antioxidants in the body.1 Oxidative stress, caused by RS, is involved into the genesis of different pathologies such as inflammatory bowel disease, cardiovascular disease, Alzheimer’s disease, diabetes and cancer.2 Nutraceuticals could be used to prevent oxidative stress as an additional health benefit along with nutrition.1 The use of exogenous antioxidants can ameliorate this stressful condition and restore the redox disequilibrium.3 Polyphenols have a potential health-promoting effect, however, show a low bioavailability.4 For this reason, synthesis of organic seleniumcompounds combined to (poly)phenolic compounds could increase the solubility and exert their potential synergistic antioxidant effects. The approach proposed consists of preparing the D-ribose derivative 1 to obtain the donor 2 then employed to produce glycoconjugates containing well known (poly)phenols through a Mitsunobu reaction.5 To assess the bioactivity of selenoglycoconjugates, DPPH and ABTS antiradical assays were performed, while the effects on cell proliferation were preliminarily investigated on SH-SY5Y cells. The phenol moiety greatly affected both the antiradical efficacy and the mitochondrial redox activity. The glycoconjugates, especially at the highest tested concentrations, exhibited cytotoxic effects lower than that of unconjugated phenolic compounds, underlining the mitigating impact of selenosugar

Citrus sinensis and Vitis vinifera Protect Cardiomyocytes from Doxorubicin-Induced Oxidative Stress: Evaluation of Onconutraceutical Potential of Vegetable Smoothies

The interest towards nutraceuticals able to counteract drug side effects is continuously growing in current chemotherapeutic protocols. In the present study, we demonstrated that smoothies containing mixtures of Citrus sinensis and Vitis vinifera L. cv. Aglianico N, two typical fruits of the Mediterranean diet, possess bioactive polyphenols that protect cardiomyocytes against doxorubicin-induced oxidative stress. The polyphenolic extracts isolated from Citrus sinensis- and Vitis vinifera-based functional smoothies were deeply characterized by Liquid Chromatography-Mass Spectrometry methods. Subsequently, the functional smoothies and relative mixtures were tested to verify their ability to affect cellular viability and oxidative stress parameters in embryonic cardiomyocyte cells (H9c2), and human breast adenocarcinoma cell line (MCF-7) exposed to doxorubicin. Interestingly, we found that the mix resulting from Citrus sinensis and Vitis vinifera association in ratio 1:1 was able to reduce cardiomyocytes damage induced by anthracyclines, without significantly interfering with the pro-apoptotic activity of the drug on breast cancer cells. These results point out the potential use of vegetable smoothies as adjuvants functional foods for chemotherapeutic anticancer protocols

Antitumor Agents. 2. Synthesis, Structure-Activity Relationships, and Biological Evaluation of Substituted 5H-Pyridophenoxazin-5-ones with Potent Antiproliferative Activity

New antiproliferative compounds, 5H-pyrido[3,2-a]phenoxazin-5-ones (1-10), 5H-benzophenoxazin- 5-one (11), 5H-pyrido[2,3-a]phenoxazin-5-one (12), 5H-pyrido[3,4-a]phenoxazin-5-one (13), and 5H-pyrido[4,3-a]phenoxazin-5-one (14), were synthesized and evaluated against representative human neoplastic cell lines. The excellent cytotoxic activity of these polycyclic phenoxazinones, structurally related to the actinomycin chromophore, is discussed in terms of structural changes made to rings A and D (Chart 1). Electron-withdrawing or electron-donating substituents were introduced at different positions of ring A to probe the electronic and positional effects of the substitution. A nitro group in R2 or in R1 increases the cytotoxic activity, whereas electron-donating methyl groups in any position lead to 10- to 100-fold decreasing of the activity. The low antiproliferative activity of benzophenoxazinone 11 and pyridophenoxazinones 13 and 14 confirms the crucial role of pyridine nitrogen in the W position of ring D in DNA binding. The unexpected high activity exhibited by 12, which has the nitrogen in the X position, could be ascribed to a different mechanism of action, which needs further investigation

N-4 Alkyl Cytosine Derivatives Synthesis: A New Approach

The selective N-4 alkylation of cytosine plays a critical role in the synthesis of biologically active molecules. This work focuses on the development of practical reaction conditions toward a regioselective synthesis of N-4-alkyl cytosine derivatives. The sequence includes a direct and selective sulfonylation at the N-1 site of the cytosine, followed by the alkylation of the amino siteusing KHMDS in CH2Cl2/THF mixture, providing a fast and efficient approach consistent withpyrimidine-based drug design

An NMR Study of the Bortezomib Degradation under Clinical Use Conditions

The (R)-3-methyl-1-((S)-3-phenyl-2-(pyrazine-2-carboxamido)propanamido)butyl-boronic acid, bortezomib (BTZ), which binds the 20S proteasome subunit and causes a large inhibition of its activity, is a peptidomimetic boronic drug mainly used for the treatment of multiple myeloma. Commercial BTZ, stabilized as mannitol derivative, has been investigated under the common conditions of the clinical use because it is suspected to be easily degradable in the region of its boronic moiety. Commercial BTZ samples, reconstituted according to the reported commercial instructions and stored at 4°C, were analyzed by high-field nuclear magnetic resonance spectroscopy in comparison with identical samples bubbled with air and argon, respectively. All the samples remained unchanged for a week. After a month, the air filled samples showed the presence of two main degradation products (6% of starting material), the N-(1-(1-hydroxy-3-methylbutylamino)-1-oxo-3-phenylpropan-2-yl) pyrazine-2-carboxamide (BTZ1; 5%, determined from NMR integration) and the (S)-N-(1-(3-methylbutanamido)-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxamide (BTZ2; 1%, determined from NMR integration), identified on the basis of their chemical and spectroscopic properties. The BTZ1 and BTZ2 finding suggests that, under the common condition of use and at 4°C, commercial BTZ-mannitol is stable for a week, and that, in time, it undergoes slow oxidative deboronation which partially inactivates the product. Low temperature and scarce contact with air decrease the degradation process

Detailed peptide profiling of “Scotta”: from a dairy waste to a source of potential health-promoting compound

“Scotta” is a liquid waste deriving from Ricotta cheese production, which is wrongly considered only a dairy by-product. In this work, with the aim to elucidate the presence of valuable bioactive compounds in Buffalo’s Scotta, a peptide fraction under 3000 Da was isolated by ultra-filtration, purified by solid-phase extraction, and,subsequently, characterized in detail by liquid chromatography coupled to Orbitrap mass spectrometry. Analytical results revealed a complex profile, leading to the identification of 226 peptides, belonging to alpha, beta, and kappa caseins. A database-driven search approach was used to assess the biological effects of some of the identified peptides. A wide range of healthy properties was ascribed to the encrypted peptides, comprising antihypertensive, antimicrobial, immunomodulating, opioid, antioxidant, and antithrombotic. The peptidomic profile of Scotta was highlighted in depth for the first time, and the results revealed that this matrix should not be considered only a mere by-product, but a source of potential health-promoting peptides, which can be recovered and employed in nutraceuticals and functional foods