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Sabrina Castellano,
Ciro Milite,
Rino Ragno,
Silvia Simeoni,
Antonello Mai,
Vittorio Limongelli,
Ettore Novellino,
Ingo Bauer,
Gerald Brosch,
Astrid Spannhoff,
Donghang Cheng,
Mark T Bedford, Gianluca Sbardella
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ABSTRACT: Here we report the synthesis of a number of compounds structurally related to arginine methyltransferase inhibitor 1 (AMI-1). The structural alterations that we made included: 1) the substitution of the sulfonic groups with the bioisosteric carboxylic groups; 2) the replacement of the ureidic function with a bis-amidic moiety; 3) the introduction of a N-containing basic moiety; and 4) the positional isomerization of the aminohydroxynaphthoic moiety. We have assessed the biological activity of these compounds against a panel of arginine methyltransferases (fungal RmtA, hPRMT1, hCARM1, hPRMT3, hPRMT6) and a lysine methyltransferase (SET7/9) using histone and nonhistone proteins as substrates. Molecular modeling studies for a deep binding-mode analysis of test compounds were also performed. The bis-carboxylic acid derivatives 1 b and 7 b emerged as the most effective PRMT inhibitors, both in vitro and in vivo, being comparable or even better than the reference compound (AMI-1) and practically inactive against the lysine methyltransferase SET7/9.
ChemMedChem 03/2010; 5(3):398-414. · 3.15 Impact Factor
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ABSTRACT: Novel triazine analogues of 5-alkyl-2-alkylthio-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydropyrimidin-4(3H)-ones (F(2)-DABOs), previously described by us as nonnucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs), were tested for their antiproliferative and cytodifferentiating activity on the A-375 human melanoma cell line. Most of the tested derivatives were effective in decreasing cell proliferation, facilitating morphological differentiation, and reprogramming gene expression. All these effects were reversible upon withdrawal of RT inhibitors. Among the compounds tested, 3 f showed the highest antiproliferative effect, whereas compound 6 c, although not affecting cell proliferation, is endowed with a strong cytodifferentiating effect, which is probably related to a marked upregulation of the e-cad gene. These results support the potential of NNRTIs as valuable antitumor agents.
ChemMedChem 11/2006; 1(10):1073-80. · 3.15 Impact Factor
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Antonello Mai, Gianluca Sbardella,
Marino Artico,
Rino Ragno,
Silvio Massa,
Ettore Novellino,
Giovanni Greco,
Antonio Lavecchia,
Chiara Musiu,
Massimiliano La Colla,
Chiara Murgioni,
Paolo La Colla,
Roberta Loddo
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ABSTRACT: 5-Alkyl-2-(alkylthio)-6-(2,6-difluorobenzyl)-3,4-dihydropyrimidin-4(3H)-ones (S-DABOs, 2) have been recently described as a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) active at nanomolar concentrations (Mai, A. et al. J. Med. Chem. 1999, 42, 619−627). In pursuing our lead optimization efforts, we designed novel conformationally restricted S-DABOs, 3, featuring a methyl at the benzylic carbon (Y = Me) and at the pyrimidine 5-position (R = Me). Conformational analyses and docking simulations suggested that the presence of both methyls would significantly reduce conformational flexibility without compromising, in the R enantiomers, the capability of fitting into the RT non-nucleoside binding pocket. To develop structure−activity relationships, we prepared several congeners of type 3 belonging to the thymine (R = Me) and uracil (R = H) series, featuring various 2-alkylthio side chains (X = Me, i-Pr, n-Bu, i-Bu, s-Bu, c-pentyl, and c-hexyl) and aryl moieties different from the 2,6-difluorophenyl (Ar = phenyl, 2,6-dichlorophenyl, 1-naphthyl). Moreover, α-ethyl derivatives (Y = Et) were included in the synthetic project in addition to α-methyl derivatives (Y = Me). All of the new compounds were evaluated for their cytotoxicity and anti-HIV-1 activity in MT-4 cells, and some of them were assayed against highly purified recombinant wild-type HIV-1 RT using homopolymeric template primers. The results were expressed as CC50 (cytotoxicity), EC50 (anti-HIV-1 activity), SI (selectivity, given by the CC50/EC50 ratio), and IC50 (RT inhibitory activity) values. In the 2,6-difluorobenzylthymine (R = Me) series, methylation of the benzylic carbon improved anti-HIV-1 and RT inhibitory activities together with selectivity. Compound 3w (Ar = 2,6-F2-Ph, R = Y = Me, X = c-pentyl) turned out the most potent and selective among the S-DABOs reported to date (CC50 > 200 μM, EC50 = 6 nM, IC50 = 5 nM, and SI > 33 333). Assays performed on the pure enantiomer (+)-3w, much more active than (−)-3w, yielded the following results: CC50 > 200 μM, EC50 = 2 nM, IC50 = 8 nM, and SI > 100 000, under conditions wherein MKC-442 was less active and selective (CC50 > 200 μM, EC50 = 30 nM, IC50 = 40 nM, SI > 6666). The 2,6-difluorophenylethylthymines (R = Me) were generally endowed with higher potency compared with the uracil counterparts (R = H). In the 2,6-difluorophenyl series the best and the least performant 2-alkylthio side chains were the 2-c-pentylthio and the 2-methylthio, respectively. When the methyl at the benzylic carbon was replaced by an ethyl, activity was retained or decreased slightly, thus suggesting that the dimensions of the cavity within the RT hosting this substituent would not be compatible with groups larger than ethyl. Aryl moieties different from the 2,6-difluorophenyl (phenyl, 1-naphthyl, 2,6-dichlorophenyl) were generally detrimental to activity, consistent with a favorable electronic effect exerted by the 2,6-fluorines on a putative charge-transfer interaction between the aromatic moieties of the inhibitor and Tyr188.
07/2001;
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ABSTRACT: Molecular modeling analysis of compounds belonging to the recently published series of dihydro-alkoxy-benzyl-oxopyrimidines (DABOs), such as S-DABOs and DATNOs, gave support to the design of new 2,6-disubstituted benzyl-DABO derivatives as highly potent and specific inhibitors of the HIV-1 reverse transcriptase (RT). To follow up on the novel DABO derivatives, we decided to investigate the effect of electron-withdrawing substituents in the benzyl unit of the S-DABO skeleton versus their anti-HIV-1 activity. Such chemical modifications impacted the inhibitory activity, especially when two halogen units were introduced at positions 2 and 6 in the phenyl portion of the benzyl group bound to C-6 of the pyrimidine ring. Various 5-alkyl-2-(alkyl(or cycloalkyl)thio)-6-(2,6-dichloro(or 2,6-difluoro)phenylmethyl)-3,4-dihydropyrimidin-4(3H)-ones were then synthesized and tested as anti-HIV-1 agents in both cell-based and enzyme (recombinant reverse transcriptase, rRT) assays. Among the various mono- and disubstituted phenyl derivatives, the most potent were those containing a 6-(2,6-difluorophenylmethyl) substituent (F-DABOs), which showed EC50's ranging between 40 and 90 nM and selectivity indexes up to ≥5000. An excellent correlation was found between EC50 and IC50 values which confirmed that these compounds act as inhibitors of the HIV-1 RT. The structure−activity relationships of the newly synthesized pyrimidinones are presented herein.
02/1999;
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ABSTRACT: 5-Amino- and 7-amino-4-hydroxy-2-naphthoic acids were synthesized for the first time via a microwave-assisted pathway. The separation of the two isomers was then conveniently achieved by exploiting their different reactivities with CDI.
Tetrahedron Letters. 48(27):4653-4655.
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Second Joint Italian-Swiss Meeting on Medicinal Chemistry;
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Frontiers in CNS and Oncology Medicinal Chemistry, ACS-EFMC;
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Second Joint Italian-Swiss Meeting on Medicinal Chemistry;
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JOURNAL OF MEDICINAL CHEMISTRY. 38(17):3258-3263.
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XXI Congresso Nazionale Della SocietaÂ’ Chimica, Italiana;
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JOURNAL OF MEDICINAL CHEMISTRY. 42(4):619-627.
