Total synthesis and pharmacological characterization of solomonsterol A, a potent marine pregnane-X-receptor agonist endowed with anti-inflammatory activity

Recently, we reported the identification of a novel class of pregnane-X-receptor (PXR) agonists, solomonsterols A and B, isolated from the marine sponge Theonella swinhoei. Preliminary pharmacological studies demonstrated that these natural compounds are potential leads for the treatment of human disorders characterized by dysregulation of innate immunity. In this article, we describe the first total synthesis of solomonsterol A and its in vivo characterization in animal models of colitis. Using transgenic mice expressing the human PXR, we found that administration of synthetic solomonsterol A effectively protects against development of clinical signs and symptoms of colitis and reduced the generation of TNFα, a signature cytokine for this disorder. In addition, we have provided the first evidence that solomonsterol A might act by triggering the expression of TGFβ and IL-10, potent counter-regulatory cytokines in inflammatory bowel diseases (IBD). Finally, we have shown that solomonsterol A inhibits NF-κB activation by a PXR dependent mechanism. In summary, solomonsterol A is a marine PXR agonist that holds promise in the treatment of inflammation-driven immune dysfunction in clinical settings.     

Design,synthesis, and evaluation of new series of Imperatorin analogs with potential vasodilatory activity

Two series of imperatorin analogs were synthesized based on our previous research and evaluated for their vasodilatation activities on in vitro rat mesenteric artery, basilar artery, and renal artery ring models. Target compounds were characterized by infrared, ¹H NMR, and mass spectra. Most derivatives possessed significant vasodilatory activity on the mesenteric artery, and compound 3a exhibited favorable and broad vasodilatation activities on three kinds of rat artery ring models. The pharmacological results indicated that introducing nitrogen-contained ring in side chain or large steric hindrance at the distal end could increase the vasodilatory activity. Further, replacement of oxygen atom (–O–) in the skeleton of furocoumarin derivatives with nitrogen (–NH–) could cause the decrease of vasodilatory activity. The molecular docking also indicated that compound 3a showed a best affinity with α-1C receptor (PDB ID: 3G43). All these results suggested compound 3a would be a potential vasodilatory agent for hypertension.     

A novel series of chlorinated plastoquinone analogs: Design,synthesis, and evaluation of anticancer activity

Herein, we report the synthesis and cytotoxic effects of novel chlorinated plastoquinone analogs ( ABQ1–17 ) against different leukemic cells. Compounds ABQ3 , ABQ11 , and ABQ12 demonstrated a pronounced antiproliferative effect against chronic myelogenous leukemia (CML) K562 cell line with IC₅₀ values of 0.82 ± 0.07, 0.28 ± 0.03, and 0.98 ± 0.22 μM, respectively. Among them, ABQ11 showed approximately three times higher selectivity than imatinib on CML. ABQ11 ‐treated CML cells induced significant apoptosis at low concentration. Inhibitory effect of ABQ11 against eight different tyrosine kinases, including ABL1, was investigated. ABQ11 inhibited ABL1 with IC₅₀ value of 13.12 ± 1.71 μM, indicating that the moderate inhibition of ABL1 kinase is just an in‐part mechanism of its outstanding cellular activity. Molecular docking of ABQ11 into ABL1 kinase ATP‐binding pocket revealed the formation of some key interactions. Furthermore, DNA cleavage assay showed that ABQ11 strongly disintegrated DNA at 1 μM concentration in the presence of iron (II) complex system, assuming that the major mechanism for the anticancer effects of ABQ11 is DNA cleavage. In silico ADMET prediction revealed that ABQ11 is a drug‐like small molecule with a favorable safety profile. Taken together, ABQ11 is a potential antiproliferative hit compound that exhibits unique cytotoxic activity distinct from imatinib.     

Novel malyngamide structural analogs: synthesis and biological evaluation

In the course of our search for new anticancer agents, a series of novel malyngamide derivatives were synthesized by sharpless asymmetric epoxidation, followed by Julia-Kocinski olefination reactions as key reaction sequence. Anticancer activities of all these derivatives were screened against IMR-32, SF-295, SKNSH, HeLa, Colon-502713, SW-620, and Hop-62 cell lines for the first time.     

Quinones. 4. Novel eicosanoid antagonists: synthesis and pharmacological evaluation

A new series of omega-phenyl-omega-quinonylalkanoic acids and related compounds was synthesized. The compounds were tested for their inhibitory effects on U-44069-induced contraction of the rabbit aorta. (+/- )-7-(3,5,6-Trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid (4d) (AA-2414) with pA2 value of 8.28 was one of the most potent compounds. Compound 4d inhibited U-46619-induced contraction of the guinea pig lung (pA2 = 8.29) and U-44069-induced aggregation of the guinea pig platelet (IC50 = 3.5 x 10(-7) M). Compound 4d displaced the binding of [3H]U-46619 to guinea pig platelets (IC50 = 7.4 x 10(-9) M). Compound 4d also showed very potent inhibitory effects with an MED of 0.3 mg/kg (po) on U-46619-, LTD4-, PAF-, or IgG1-induced bronchoconstriction in guinea pigs. The enantiomers of 4d were prepared. The R-(+) isomer 8a was active in both in vitro and in vivo tests, but the S-(-) isomer 8b was much less active. We concluded that the antiasthmatic effects of 4d were based mainly on the TXA2 receptor antagonistic action. In addition, compound 4d showed potent inhibitory effects on PGD2-, PGF2 alpha-, and 11-epi-PGF2 alpha-induced contraction of the guinea pig tracheal strips. The diverse inhibitory effects might be expressed in terms of eicosanoid-antagonistic activity.     

Novel analgesic/anti-inflammatory agents: diarylpyrrole acetic esters endowed with nitric oxide releasing properties

The design of compounds that are able to inhibit cyclooxygenase (COX) and to release nitric oxide (NO) should give rise to drugs endowed with an overall safer profile for the gastrointestinal and cardiovascular systems. Herein we report a new class of pyrrole-derived nitrooxy esters (11a-j), cyclooxygenase-2 (COX-2) selective inhibitors endowed with NO releasing properties, with the goal of generating new molecules able to both strongly inhibit this isoform and reduce the related adverse side effects. Taking into account the metabolic conversion of nitrooxy esters into corresponding alcohols, we also studied derivatives 12a-j. All compounds proved to be very potent and selective COX-2 inhibitors; nitrooxy derivatives displayed interesting ex vivo NO-dependent vasorelaxing properties. Compounds 11c, 11d, 12c, and 12d were selected for further in vivo studies that highlited good anti-inflammatory and antinociceptive activities. Finally, two selected compounds (11c and 12c) tested in human whole blood (HWB) assay proved to be preferential inhibitors of COX-2.     

Design,synthesis, physicochemical,and pharmacological evaluation of gallic acid esters as non-ulcerogenic and gastroprotective anti-inflammatory agents

In our effort to identify the effective gastric sparing and protective anti-inflammatory agents, a series of gallic acid esters were synthesized, characterized, and studied to assess their physicochemical properties. Subsequently, the esters were evaluated for their anti-inflammatory activity and effect on gastric mucosa by most active compounds. All the compounds exhibited promising anti-inflammatory activity in carrageenan-induced rat paw edema model. In particular, 7a, 7c, 7f, and 7h emerged as the most active compounds in the series. The findings of gastric ulcer and antioxidant studies suggested these compounds as non-ulcerogenic and gastroprotective. Further, the predicted ADME properties of all the tested compounds were found to be in the ranges as predicted by QikProp for 95 % of known oral drugs and also satisfy the Lipinski’s rule of five.     

Novel 4(3H)-quinazolinone analogs: synthesis and anticonvulsant activity

A new series of quinazoline analogs was designed, synthesized, and evaluated for their anticonvulsant activity. Compounds 6, 12, 21, 36, 37, and 38 showed 70–100 % protection against PTZ-induced seizures acting as GABA_A receptor agonists. Compound N-(3,4,5,6-tetrachloro-phthalimido)-2-[(3-phenyl-4-oxo-6-methyl-3H-quinazolin-2-yl)-thio]acetamide (12) representing the moderate active compounds and 2-[6-iodo-4-oxo-2-(thiophen-2-yl)-quinazolin-3(4H)-yl]-isoindoline-1,3-dione (38) representing the remarkably active compounds in this stud, showed ED₅₀ values of 457 and 251 mg/kg; TD₅₀ values of 562 and 447 mg/kg; PI values of 1.22 and 1.78, LD₅₀ values of 1,288 and 1,380 mg/kg, and TI values of 2.82 and 5.50, respectively. Compound 38 proved to be almost twofold more active than the standard drug sodium valproate.     

New potential antihistaminic compounds. Virtual combinatorial chemistry, computational screening, real synthesis, and pharmacological evaluation

To study the utility of the virtual combinatorial chemistry coupled with computational screening, a library of amine and urea derivatives was designed by virtual combinatorial synthesis and eventually computationally screened by a mathematical topological model as antihistaminic compounds. The results reveal that virtual combinatorial synthesis and virtual screening together with molecular topology are a powerful tool in the design of new drugs.     

Synthesis and anti-inflammatory evaluation of novel paclitaxel analogs

A series of paclitaxel analogs modified at C-3′-N and C-7 positions were synthesized from baccatin III and their structures were confirmed by ¹H-NMR, ¹³C-NMR, HR-MS. Compound 7e exhibited potent ability to decrease TNFα (tumor necrosis factor α) in the LPS-activated RAW264.7 murine macrophage-like cell line. The preliminary data indicated that the anti-inflammatory effects may be related to MD-2 and Toll-like receptor 4 (TLR4), rather than Toll-like receptor 2 (TLR2).     

Design, synthesis, and anti-inflammatory evaluation of a series of novel amino acid-binding 1,5-diarylpyrazole derivatives

Aim: To design and synthesize a series of novel amino acid-binding 1,5-diarylpyrazole derivatives, which are intended to act as prodrugs with better aqueous solubility than celecoxib, and which will exert potent anti-inflammatory activi-ties after being converted to their parent compounds in vivo. Methods: To introduce an amino acid, celecoxib analogs containing amino or methylamino group were synthesized first through multi-step chemical reactions. All the synthesized compounds were screened in an intact cell-based assay in vitro and in carrageenan-induced mouse paw edema in vivo. Some active compounds were selected for further evaluation in a carrageenan-induced rat paw edema model. The preliminary pharmacokinetics experiments were conducted using high performance liquid chromatography/mass spectrometry (HPLC/MS). Results: Celecoxib, 6 of the 1,5-diarylpyrazole class of celecoxib analogs, and their amino acid derivatives (hydrochloride salts) were synthesized. In vitro screening, the hydrochloride salts showed decreased inhibitory effects on cyclooxygenase (COX)- 1 and COX-2 compared with their parent compounds, but some exhibited potent anti-inflammatory activity in vivo. Compound 4a was selected for further evaluation, and its anti-inflammatory effect was equivalent to that of celecoxib after oral administration in the carrageenan-induced rat paw edema model. At three doses (25 mg/kg, 50 mg/kg, and 100 mg/kg) the percentage inhibition on edema was 20.7%, 52.6%, and 62.6% (for compound 4a) and 27.8%, 38.4%, and 40.1% (for celecoxib), respectively. Preliminary pharmacokinetic evaluations support the hypothesis that compound 4a was actually converted to its parent compound, compound 4. Conclusion: The compound bound with amino acid acts like prodrug, which can exert anti-inflammatory effect similar to celecoxib after being converted to its parent compound. This finding will be of great benefit in carrying out structural modifications of prodrug-like selective COX-2 inhibitors.