A Global Scale Scenario for Prebiotic Chemistry: Silica-Based Self-Assembled Mineral Structures and Formamide

The pathway from simple abiotically made organic compounds to the molecular bricks of life, as we know it, is unknown. The most efficient geological abiotic route to organic compounds results from the aqueous dissolution of olivine, a reaction known as serpentinization (Sleep, N.H., et al. (2004) <i>Proc. Natl. Acad. Sci. USA</i> 101, 12818–12822). In addition to molecular hydrogen and a reducing environment, serpentinization reactions lead to high-pH alkaline brines that can become easily enriched in silica. Under these chemical conditions, the formation of self-assembled nanocrystalline mineral composites, namely silica/carbonate biomorphs and metal silicate hydrate (MSH) tubular membranes (silica gardens), is unavoidable (Kellermeier, M., et al. In <i>Methods in Enzymology, Research Methods in Biomineralization Science</i> (De Yoreo, J., Ed.) Vol. 532, pp 225–256, Academic Press, Burlington, MA). The osmotically driven membranous structures have remarkable catalytic properties that could be operating in the reducing organic-rich chemical pot in which they form. Among one-carbon compounds, formamide (NH₂CHO) has been shown to trigger the formation of complex prebiotic molecules under mineral-driven catalytic conditions (Saladino, R., et al. (2001) <i>Biorganic & Medicinal Chemistry</i>, 9, 1249–1253), proton irradiation (Saladino, R., et al. (2015) <i>Proc. Natl. Acad. Sci. USA</i>, 112, 2746–2755), and laser-induced dielectric breakdown (Ferus, M., et al. (2015) <i>Proc Natl Acad Sci USA</i>, 112, 657–662). Here, we show that MSH membranes are catalysts for the condensation of NH₂CHO, yielding prebiotically relevant compounds, including carboxylic acids, amino acids, and nucleobases. Membranes formed by the reaction of alkaline (pH 12) sodium silicate solutions with MgSO₄ and Fe₂(SO₄)₃·9H₂O show the highest efficiency, while reactions with CuCl₂·2H₂O, ZnCl₂, FeCl₂·4H₂O, and MnCl₂·4H₂O showed lower reactivities. The collections of compounds forming inside and outside the tubular membrane are clearly specific, demonstrating that the mineral self-assembled membranes at the same time create space compartmentalization and selective catalysis of the synthesis of relevant compounds. Rather than requiring odd local conditions, the prebiotic organic chemistry scenario for the origin of life appears to be common at a universal scale and, most probably, earlier than ever thought for our planet

Benzodeazaoxaflavins as Sirtuin Inhibitors with Antiproliferative Properties in Cancer Stem Cells

Inhibition of sirtuins has recently been proposed as a promising anticancer strategy. Some of the new benzodeazaoxaflavins (<b>2a</b>, <b>2b</b>, and <b>2d</b>) here reported as SIRT1/2 inhibitors were endowed with pro-apoptotic properties in human U937 leukemia cells and, most importantly, together with the prototype MC2141 (<b>1</b>) displayed antiproliferative effects in cancer stem cells from patients with colorectal carcinoma and glioblastoma multiforme, known to be highly tumorigenic, resistant to conventional cancer chemotherapy, and responsible, at least in part, for cancer relapse or recurrence

2-(Alkyl/Aryl)Amino-6-Benzylpyrimidin-4(3<i>H</i>)-ones as Inhibitors of Wild-Type and Mutant HIV-1: Enantioselectivity Studies

The single enantiomers of two pyrimidine-based HIV-1 non-nucleoside reverse transcriptase inhibitors, <b>1</b> (MC1501) and <b>2</b> (MC2082), were tested in both cellular and enzyme assays. In general, the <i>R</i> forms were more potent than their <i>S</i> counterparts and racemates and (<i>R</i>)-<b>2</b> was more efficient than (<i>R</i>)-<b>1</b> and the reference compounds, with some exceptions. Interestingly, (<i>R</i>)-<b>2</b> displayed a faster binding to K103N RT with respect to WT RT, while (<i>R</i>)-<b>1</b> showed the opposite behavior

Discovery of Salermide-Related Sirtuin Inhibitors: Binding Mode Studies and Antiproliferative Effects in Cancer Cells Including Cancer Stem Cells

Chemical changes performed on <b>1a</b> (sirtinol) led to a series of SIRT1/2 inhibitors, in some cases more potent than <b>1a</b> mainly against SIRT1. Tested in human leukemia U937 cells, the benzamide and anilide derivatives <b>1b</b>, <b>1c</b>, <b>2b</b>, and <b>2c</b> as well as the 4-(2-phenylpropyl)­thioanalogue <b>4c</b> showed huge apoptosis induction, while some sulfinyl and sulfonyl derivatives (<b>5b</b>, <b>5c</b>, and <b>6a</b>–<b>c</b>) were highly efficient in granulocytic differentiation. When assayed in human leukemia MOLT4 as well as in human breast MDA-MB-231 and colon RKO cancer cell lines, the anilide <b>2b</b> (salermide) and the phenylpropylthio analogue <b>4b</b> emerged as the most potent antiproliferative agents. Tested on colorectal carcinoma and glioblastoma multiforme cancer stem cells (CSCs) from patients, <b>2b</b> was particularly potent against colorectal carcinoma CSCs, while <b>4b</b>, <b>6a</b>, and the SIRT2-selective inhibitor AGK-2 showed the highest effect against glioblastoma multiforme CSCs. Such compounds will be further explored for their broad-spectrum anticancer properties