Letters in Drug Design & Discovery - Volume 5, Issue 2, 2008

The present CoMFA study on thiazolidine-2,4-diones attempts to quantitatively describe the structural features of the compounds for high PPAR-γ agonistic action. A set of 50 compounds was used for the analysis. A training set and a test set were designed consisting of 39 and 11 compounds, respectively. All the molecules were modeled and energy minimized using SYBYL 6.7 software. The molecules were aligned using the most active analog as the template by field fit method. PLS (partial least square) analysis was performed on the training set and statistical parameters like q2, r2, F value and P value were calculated. A final model was generated by excluding four outliers from the training set. Cross Validation was done by leave one out method. The developed CoMFA model showed a good external as well as internal predictivity in most of the compounds with low residual values. The q2 value of the developed model was 0.549 and r2 value was 0.976. Contour plots generated from the steric and electrostatic contributions of this model were used to derive structure-activity relationships and to design a hypothetical molecular structure, which can be used as a lead for design and syntheses of newer molecules.

This article presents a review on artepillin C, a diprenyl-p-hydroxycinnamic acid derivative mainly isolated from Baccharis species, and one of the principal phenolic acids present in Brazilian propolis, covering aspects of its occurrence, synthesis, biological activities and pharmacokinetics.

Bromo- and alkoxymethyl-furocoumarins were synthesized and evaluated for their ability to photoinduce cell death in human tumoral cell culture. Bromo substituted compounds resulted to be the most phototoxic compounds giving rise to a significant induction of apoptosis at 24 h from irradiation as demonstrated by a remarkable percentage of Annexin- V positive cells. The DNA photocleavaging properties of these derivatives were investigated using plasmid DNA as model. The results indicate that bromo derivatives induce significant photodamage to DNA. In particular, the effect is strongly evidenced after treatment of photosensitized DNA by two base excision repair enzymes, Fpg and Endo III.

Linear peptide analogs of complestatin were synthesized via solid phase peptide synthesis and tested in vitro as inhibitors against N-methyl-D-aspartic acid (NMDA) neurotoxicity as possible new peptidic neuroprotectants. While none of the analogs were as potent as the parent compound (IC50 = 2.5 μM), hexamer 11c and heptamer 1c, which contain all D-amino acids, showed modestly potent neuroprotective effects with IC50 values of 23.8 μM and 22.5 μM, respectively. The results indicate that the bicyclic ring structure of complestatin plays an important role for its inhibitory activity, and the D-stereochemistry of tryptophan (component F) is important for the potency of the linear peptide analogs.

Four known small molecule uracil-DNA glycosylase (UNG) inhibitors were synthesized and tested against human melanoma cells, IgR3 and MM200. They were found to be effective against cell proliferation at micromolar concentrations and to operate through a nonapoptotic mechanism. Thus, small molecules that target UNG may be useful as potential chemotherapeutic agents against human melanoma.

In research for a new immunomodulator, we discoverd a novel hydroxypiperidine derivative 9h which was a potent inhibitor of IL-15induced T cell activation. Further modification of 9h gave a potent and orally active agent 10 which was effective in a mouse CIA model.

We have explored a series of spirocyclic piperidine amide derivatives with respect to the N-acyl portion (viz. 6) for inhibition of tryptase. Thus, we identified analogues 6nn and 6oo as potent tryptase inhibitors (IC50 < 10 nM) with excellent selectivity vs. trypsin. Other interesting compounds (IC50 = 10-20 nM) in this chemical series are 6k, 6m, 6ff, and 6bbb. X-ray co-crystal structures of 6nn•tryptase and 6pp•tryptase are reported.

Intramolecular N-7 alkylation of 6-substituted purines gave rise to a new series of tricyclic purine derivatives. The new compounds were evaluated for their cytotoxicity, their antileishmania activity together with their capacity to modulate NO production in macrophages. As a result compound 1 exhibited a modest activity against KB cells. On the other hand 4a was active against Leishmania and it diminished NO production of BCG-induced J774A.1 cells.

In this work we reported the design, synthesis and evaluation of the new diaryl heterocyclic derivatives based on the lead compounds of Rofecoxib and Celecoxib by application of the principle of isosterism. The in vivo pharmacological evaluation of these new compounds lead us to select the compounds (Ia) and (IIc) as a new prototype which a substituent ortho to the methylsulfone or sulfonamide group was introduced for further development, more active that celecoxib at the same mass concentration.

Mycophenolate mofetil, an inosine monophosphate dehydrogenase inhibitor, that inhibits the de novo pathway of guanosine nucleotide synthesis, inhibits proliferative responses of T and B lymphocytes as well as antibody production by B-lymphocytes. It is indicated for the prophylaxis of organ rejection after allogeneic cardiac, hepatic and renal transplants. It has also been recently used with good success in patients with lupus nephritis. Based on these actions mycophenolate mofetil appears to be a novel agent in the treatment of systemic sclerosis.

The present article describes a series of eighteen N'-[(E)-(hydroxy, methoxy and ethoxy substitutedphenyl) methylidene]isonicotinohydrazide derivatives, which were synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis, and the activity expressed as the minimum inhibitory concentration (MIC) in μg/ml. Compounds 2a, 2d-f, and 2h exhibited a significant activity (0.31-1.25 μg/ml) when compared with first line drugs such as isoniazid (INH) and rifampicin (RIP) and could be a good start point to find new lead compounds in the fight against multi-drug resistant tuberculosis.

Chemotherapeutic options for androgen-independent prostate cancer are extremely limited with minimum survival advantage. The benzyl-substituted unbridged titanocene bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) was tested in vitro against the human prostate cancer androgen-independent cell, PC-3, which demonstrated an IC50 value of 56 x 10-6 mol/L compared to 5.6 x 10-6 mol/L for cisplatin. Then Titanocene Y was given at the maximum tolerable dose of 40 mg/kg/d on five consecutive days to one cohort of eight PC3 tumor-bearing male NMRI:nu/nu mice, while a second cohort was treated similarly with 3 mg/kg/d of cisplatin. Both of these mouse cohorts showed a statistically significant tumor growth reduction with respect to the third solvent-treated control group, which led to T/C values of 42% for cisplatin and 52% for Titanocene Y at the end of the experiment. This encouraging activity of Titanocene Y against prostate tumors in vivo, which is almost comparable with respect to cisplatin hopefully leads to further development of Titanocene Y in the future.

The present investigation was focused on the effects induced by haloperidol and apomorphine on the antinociception induced by DAMGO (highly selective μ-agonist), U50-488H (highly selective k-agonist) and deltorphin II (highly selective δ-agonists). Haloperidol (a dopamine receptor antagonist) and apomorphine (a dopamine receptor agonist) (0.1-1.0-2.0 mg/kg/i.p.) per se did not change the pain threshold of mice both in the hot plate and in the tail flick test. The antinociception effects of DAMGO (5 mg/kg/i.p.), U50-488H (5 mg/kg/i.p.) and deltorphin II (10 ng/i.c.v./mouse) peaked by 15 min after treatment and was antagonized by haloperidol in a dose dependent manner. By contrast, the dopamine receptor agonist, apomorphine, depending on the doses used, exhibited opposite effects on opiate antinociception. Treatment of mice with low doses of apomorphine (0.1-1.0 mg/kg/i.p.) reduces the antinociception induced by μ, k and δ receptor agonists whereas a high dose (2 mg/kg/i.p.) potentiates it. Our results indicate that dopamine receptors are involved in the control of antinociception at both the μ, k and δ receptor level.

Abdominal aortic surgery is relatively common associated with considerable postoperative morbidity and mortality. The aortic cross-clamping for the implantation of a vascular prosthetic graft induces a systemic inflammatory response (SIR) because of an ischemia-reperfusion (IR) injury. In our experimental models we have reported that propofol anesthesia, compared with sevoflurane, after IR modulates SIR and this effect might result in renal protection.