Thiazole- and imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase

Mimetics of the C-terminal CAAX tetrapeptide of Ras protein were designed replacing internal dipeptide AA with 4-amino-2-phenylbenzoic acid and cysteine (C) with 2-amino-4-thiazolyl-, 2-mercapto-4-thiazolyl-, 2-mercapto-4-imidazolyl- and 2-methylmercapto-4-thiazolyl-acetic or propionic acid. The compound in which C is replaced by 2-amino-4-thiazolylacetic acid inhibited FTase activity in the low nanomolar range and showed antiproliferative effect on rat aortic smooth muscle cells interfering with Ras farnesylation. On the basis of these results, 2-aminothiazole can be considered as an alternative to heterocycles, such as pyridine and imidazole, normally used in FTase inhibitors designed as non-thiol CAAX mimetics.     

Design and biological activity of imidazole-containing peptidomimetics with a broad-spectrum antioxidant activity

Histidine-containing natural dipeptides, such as L-carnosine, were reported to be effective against different oxygen-derived free radicals, and also lipoperoxyl radicals. However, L-carnosine appeared to be uneffective in vivo, due to the presence of ubiquitous specific or semi-specific hydrolytic enzymes. Therefore, a series of peptidomimetics were synthesized in order to confer resistance to enzymatic hydrolysis. Some structural modifications were also done in an attempt to improve the antioxidant power of the molecule, for example, in relation to binding of ferrous ions. The following methods were used for the evaluation of peptidomimetics:– The resistance to enzymatic deactivation was determined using either a purified specific enzyme or a multi-enzymatic system.– The free radical scavenging potential was measured by different in vitro methods involving different free radical species and biological targets.– Deactivation of lipid hydroperoxides was monitored by HPLC and protection of membrane phospholipids and proteins was demonstrated.– The effectiveness of peptidomimetics in vivo was evaluated.It was shown that decarboxylation of L-carnosine results in an important improvement of the resistance towards hydrolytic enzymes. In vitro experiments have demonstrated, for a series of peptidomimetics, free radical scavenging and lipid hydroperoxide deactivating properties similar to or even better than the natural peptide (depending on the experimental design). In addition, the two peptidomimetics -alanylhistamine and L-prolylhistamine proved to be far superior in inhibiting the lipid hydroperoxide-mediated cross-linking of a representative protein. Finally, -alanylhistamine was able to protect skin enzymes from UV-induced degradation in vivo.     

Towards the synthesis of bisubstrate inhibitors of protein farnesyltransferase: Synthesis and biological evaluation of new farnesylpyrophosphate analogues

Protein farnesyltransferase (FTase) has recently appeared as a new target of parasitic diseases, a field poor in drugs in development. With the aim of creating new bisubstrate inhibitors of FTase, new farnesyl pyrophosphate analogues have been studied. Farnesyl analogues with a malonic acid function exhibited the best inhibitory activity on FTase. This group was introduced into our imidazole-containing model leading to new compounds with submicromolar activities. Kinetic experiments have been realized to determine their binding mode to the enzyme.     

Novel and selective imidazole-containing biphenyl inhibitors of protein farnesyltransferase

A series of imidazole-containing biphenyls was prepared and evaluated in vitro for inhibition of FTase and cellular Ras processing. Several of these analogues, such as 21, are potent inhibitors of FTase (<1nM), FTase/GGTase selective (>300-fold) and cellularly active (相似文献   

Synthesis and biological evaluation of trisubstituted imidazole derivatives as inhibitors of p38alpha mitogen-activated protein kinase

A series of trisubstituted imidazole derivatives containing a 4-fluorophenyl group, a pyrimidine ring, and a CN- or CONH₂-substituted benzyl moiety have been synthesized and evaluated for p38α MAP kinase inhibitory activity. Among them, compounds 22c, 27b, and 28b inhibited p38α MAP kinase with IC₅₀ values 27.6, 28, and 31 nM, respectively.     

In vitro and in vivo antimalarial activity of peptidomimetic protein farnesyltransferase inhibitors with improved membrane permeability

A series of protein farnesyltransferase inhibitor ester prodrugs of FTI-2148 (17) were synthesized in order to evaluate the effects of ester structure modification on antimalarial activity and for further development of a farnesyltransferase inhibitor with in vivo activity. Evaluation against P. falciparum in red blood cells showed that all the investigated esters exhibited significant antimalarial activity, with the benzyl ester 16 showing the best inhibition (ED₅₀ = 150 nM). Additionally, compound 16 displayed in vivo activity and was found to suppress parasitemia by 46.1% at a dose of 50 mg kg⁻¹ day⁻¹ against Plasmodium berghei in mice. The enhanced inhibition potency of the esters is consistent with improved cell membrane permeability compared to that of the free acid. The results of this study suggest that protein farnesyltransferase is a valid antimalarial drug target and that the antimalarial activity of these compounds derives from a balance between the hydrophobic character and the size and conformation of the ester moiety.     

Senolytic activity of piperlongumine analogues: Synthesis and biological evaluation

Selective clearance of senescent cells (SCs) has emerged as a potential therapeutic approach for age-related diseases, as well as chemotherapy- and radiotherapy-induced adverse effects. Through a cell-based phenotypic screening approach, we recently identified piperlongumine (PL), a dietary natural product, as a novel senolytic agent, referring to small molecules that can selectively kill SCs over normal or non-senescent cells. In an effort to establish the structure-senolytic activity relationships of PL analogues, we performed a series of structural modifications on the trimethoxyphenyl and the α,β-unsaturated δ-valerolactam rings of PL. We show that modifications on the trimethoxyphenyl ring are well tolerated, while the Michael acceptor on the lactam ring is critical for the senolytic activity. Replacing the endocyclic C2–C3 olefin with an exocyclic methylene at C2 render PL analogues 47–49 with increased senolytic activity. These α-methylene containing analogues are also more potent than PL in inducing ROS production in WI-38 SCs. Similar to PL, 47–49 reduce the protein levels of oxidation resistance 1 (OXR1), an important oxidative stress response protein that regulates the expression of a variety of antioxidant enzymes, in cells. This study represents a useful starting point toward the discovery of senolytic agents for therapeutic uses.     

Synthesis and biological evaluation of a new series of N-ylides as protein farnesyltransferase inhibitors

A new family of 30 benzoylated N-ylides 4 and 5 was synthesized and evaluated for the inhibitory activity on human protein farnesyltransferase. Most of these novel compounds possessed in vitro inhibition potencies in the micromolar range. The nature of the substituents on the pyridine and phenyl units proved to be important in determining inhibitory activity and generally, the replacement of the cyanoacrylonitrile function by a cyanoethylacrylate group decreased the biological potential on farnesyltransferase. These results completed our SAR study on this original class of N-ylides.     

Synthesis,crystal structure and biological activity of novel analogues of tricyclic drugs

A series of fourteen novel, eight-membered lactam- and dilactam-based analogues of tricyclic drugs were obtained in a simple one-pot procedure. Crystal structures of two compounds were determined by single-crystal X-ray diffraction analysis and their selected structural features were discussed and compared with those of imipramine and dibenzepine. Affinity of developed molecules for histamine receptor H₁, serotonin receptors 5-HT_1A, 5-HT_2A, 5-HT₆, 5-HT₇, serotonin transporter (SERT) and dopamine receptor D₂ was determined. The commercial drug dibenzepine was also checked on these molecular targets, as its mechanism of action is largely unknown. Two derivatives of 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one (7,8) and two of dibenzo[b,f]azocin-6(5H)-one (9,10) were found to be active toward the H₁ receptor in sub-micromolar concentrations.     

Synthesis of aristolactam analogues and evaluation of their antitumor activity

A series of natural aristolactams and their analogues have been prepared and evaluated for antitumor activity against human cancer cells, including multi-drug resistant cell lines. Naturally occurring aristolactams, such as aristolactam BII (cepharanone B), aristolactam BIII, aristolactam FI (piperolactam A), N-methyl piperolactam A, and sauristolactam showed moderate antitumor activities in selected cell lines. However, several synthetic aristolactam derivatives exhibited potent antitumor activities against a broad array of cancer cell lines with GI₅₀ values in the submicromolar range.     

Synthesis and biological evaluation of novel triptolide analogues for anticancer activity

Three types of novel triptolide analogues with 9,11-olefin (3–5), five-membered unsaturated lactam ring (6–7) or A/B cis ring junction (8–14) were synthesized. Although with 9,11-olefin instead of 9,11-β-epoxide, compound 4a was much more active than the parent natural triptolide (1) with the lowest IC₅₀ value of 0.05 nM for SKOV-3 cells, clearly challenging the traditional viewpoint on the necessity of 9,11-β-epoxide group of triptolide. In addition, structure–activity relationships for three classes of compounds were studied.     

Nonidentical subunits of p21H-ras farnesyltransferase. Peptide binding and farnesyl pyrophosphate carrier functions

The protein farnesyltransferase purified from rat brain contains two nonidentical subunits, alpha and beta. The holoenzyme forms a stable complex with [3H]farnesyl pyrophosphate (FPP) that can be isolated by gel filtration. The [3H]FPP is not covalently bound to the enzyme; it is released unaltered when the enzyme is denatured. When incubated with an acceptor such as p21H-ras, the complex transfers [3H]farnesyl from the bound [3H]FPP to the ras protein. This transfer is not sensitive to dilution by unbound FPP, suggesting that the [3H]FPP is bound at a site that leads to direct transfer to the p21H-ras acceptor. Cross-linking studies show that the p21H-ras binds to the lower molecular weight subunit (beta-subunit), raising the possibility that the [3H]FPP binds to the alpha-subunit. If this suggestion can be confirmed, it would invoke a reaction mechanism in which the alpha-subunit acts as a prenyl pyrophosphate carrier that delivers FPP to p21H-ras which is bound to the beta-subunit.     

Synthesis and biological evaluation of novel hydroxybenzaldehyde-based kojic acid analogues as inhibitors of mushroom tyrosinase

Two series of novel kojic acid analogues (4a–j) and (5a–d) were designed and synthesized, and their mushroom tyrosinase inhibitory activities was evaluated. The result indicated that all the synthesized derivatives exhibited excellent tyrosinase inhibitory properties having IC₅₀ values in the range of 1.35 ± 2.15–17.50 ± 2.75 μM, whereas standard inhibitor kojic acid have IC₅₀ values 20.00 ± 1.08 μM. Specifically, 5-phenyl-3-[5-hydroxy-4-pyrone-2-yl-methylmercap-to]-4-(2,4-dihydroxyl-benzylamino)-1,2,4-triazole (4f) exhibited the most potent tyrosinase inhibitory activity with IC₅₀ value of 1.35 ± 2.15 μM. The kinetic studies of the compound (4f) demonstrated that the inhibitory effects of the compound on the tyrosinase were belonging to competitive inhibitors. Meanwhile, the structure-activity relationship was discussed.     

Grignard-mediated synthesis and preliminary biological evaluation of novel 3-substituted farnesyl diphosphate analogues

A series of substituents was installed at the 3 position of farnesyl diphosphate through a copper-cyanide mediated coupling of a vinyl triflate with various Grignard reagents. These novel FPP mimetics were then evaluated as inhibitors of or substrates for mammalian protein farnesyl transferase. The IC50 values for these compounds range from 18 to 10,100 nm, with the 3-isopropenyl analogue being one of the most potent FPP-mimetic mFTase inhibitors yet synthesized.     

Synthesis and biological evaluation of hydrazidomycin analogues

Hydrazidomycin A is an unusual secondary metabolite of Streptomyces atratus that features a rare enehydrazide core. To learn more about structure–activity relationships of the reported cytotoxic and antiproliferative agent several synthetic routes were explored to synthesize a variety of hydrazidomycin derivatives. Specifically, the size of the side chains, the nature of the double bond and the polar head group were altered. Overall, fourteen analogues were tested for their cytotoxic and antiproliferative effects. Re-examination of synthetic hydrazidomycin A suggests that the antiproliferative activity is attributed to a yet unknown compound that results from degradation or rearrangement. Several of the less complex analogues, however, show antiproliferative activities against individual cancer cell lines and turned out to be more potent than hydrazidomycin A.     

Synthesis and biological evaluation of helioxanthin analogues

Helioxanthin and analogues have been demonstrated to suppress gene expression of human hepatitis B virus. In the continuous attempt to optimize antiviral activity, various structural motifs were grafted on the helioxanthin scaffold. Many such analogues were synthesized and evaluated for their anti-hepatitis B virus activity. Structure–activity relationships of these helioxanthin derivatives are also discussed. Among these new compounds, 15 exhibits the highest activity against HBV (EC₅₀ = 0.06 μM). This compound can suppress viral surface antigen and DNA expression. Furthermore, viral RNA is also diminished while the core promoter is deactivated upon treatment by 15. A plausible working mechanism is postulated. Our results establish helioxanthin lignans as potent anti-HBV agents with unique mode of action. Since their antiviral mechanism is distinct from current nucleoside/nucleotide drugs, helioxanthin lignans constitute a potentially new class of anti-HBV agents for combination therapy.     

Synthesis and biological evaluation of gambierol analogues

Gambierol is a polycyclic ether toxin, isolated as a toxic constituent from the marine dinoflagellate Gambierdiscus toxicus. We describe here the synthesis and biological evaluation of structural analogues of gambierol. The present preliminary structure-activity relationship studies clearly indicate that the H ring functionality and the unsaturated side chain of gambierol are crucial for its potent toxicity.     

Synthesis and evaluation of a novel series of farnesyl protein transferase inhibitors as non-peptidic CAAX tetrapeptide analogues

A novel series of compounds, derived from 4-amino-phenyl piperazine, has been designed to selectively inhibit farnesyl protein transferase (FPTase) as CAAX tetrapeptide analogues. Certain of these compounds were shown to possess low nanomolar inhibitory activity both against the isolated enzyme and in cultured cells.     

Synthesis of pseudo-peptide analogues of the C-terminal tetrapeptide of gastrin and evaluation of their biological activity on acid secretion

The syntheses of pseudo-tetrapeptides Boc-Trp-psi (CH2-NH)-Met-Asp-Phe-NH2 21 and Boc-Trp-Met-psi (CH2-NH)-Asp-Phe-NH2 20, representing the C-terminal tetrapeptide sequence of gastrin, in which amide bonds were replaced by CH2-NH bond, are described, as well as the syntheses of pseudo-peptide analogues Boc-Trp-psi (CH2-NH)-Nle-Asp-Phe-NH2 16, Boc-Trp-Nle-psi (CH2-NH)-Asp-Phe-NH2 11, and Boc-Trp-Nle-Asp-psi (CH2-NH)-Phe-NH2 5, in which the methionyl residue was replaced by a norleucyl residue. Pseudo-peptides 16 and 21, in which the amide bond between Trp and Met (or Nle) was substituted by a CH2-NH bond, stimulated gastric acid secretion in the rat in vivo. Pseudo-peptides 11 and 20, where the amide bond between Met (or Nle) and Asp was replaced by a CH2-NH bond, did not exhibit any activity on acid secretion in the rat in vivo but were potent inhibitors of pentagastrin-induced acid secretion. Peptides 11, 16, 20 and 21 all recognize the gastrin receptor on a mucosal cell preparation. Pseudo-peptide 5, in which the amide bond between Asp and Phe was replaced by a CH2-NH bond, was a less potent inhibitor of pentagastin-induced acid secretion and had a weaker affinity than the other pseudo-peptides.