The inhibition of Aurora kinases in order to arrest mitosis and subsequently inhibit tumor growth via apoptosis of proliferating cells has generated significant discussion within the literature. We ...report a novel class of Aurora kinase inhibitors based upon a phthalazinone pyrazole scaffold. The development of the phthalazinone template resulted in a potent Aurora-A selective series of compounds (typically >1000-fold selectivity over Aurora-B) that display good pharmacological profiles with significantly improved oral bioavailability compared to the well studied Aurora inhibitor VX-680.
A computer-based method was developed for rapid and automatic identification of potential “frequent hitters”. These compounds show up as hits in many different biological assays covering a wide range ...of targets. A scoring scheme was elaborated from substructure analysis, multivariate linear and nonlinear statistical methods applied to several sets of one and two-dimensional molecular descriptors. The final model is based on a three-layered neural network, yielding a predictive Matthews correlation coefficient of 0.81. This system was able to correctly classify 90% of the test set molecules in a 10-times cross-validation study. The method was applied to database filtering, yielding between 8% (compilation of trade drugs) and 35% (Available Chemicals Directory) potential frequent hitters. This filter will be a valuable tool for the prioritization of compounds from large databases, for compound purchase and biological testing, and for building new virtual libraries.
A major impediment in the optimal selection of cancer patients for the most effective therapy is the lack of suitable biomarkers that foretell the response of a patient to a given drug. In the ...present study, we have used large-scale RNA interference-based genetic screens to find candidate biomarkers of resistance to a new acyl sulfonamide derivative, R3200. This compound inhibits the proliferation of tumor cells in vitro and in vivo, but its mechanism of action is unknown.
We used a large-scale RNA interference genetic screen to identify modulators of the efficacy of R3200. We searched for genes whose suppression in an in vitro cell system could cause resistance to the anticancer effects of R3200.
We report here that knockdown of either RBX1 or DDB1 causes resistance to the anticancer effects of R3200, raising the possibility that these two genes may have utility as biomarkers of response to this drug in a clinical setting. Interestingly, both RBX1 and DDB1 are part of an E3 ubiquitin ligase complex.
We propose that suppression of the activity of a RBX1 and DDB1-containing E3 ligase complex leads to the stabilization of certain proteins, the increased abundance of which is in turn responsible for resistance to R3200. Moreover, our data suggest that RBX1 and DDB1 could potentially be developed into biomarkers of resistance to acyl sulfonamide-based cancer drugs. This will require clinical validation in a series of patients treated with R3200.
The structural features of a new class of non-nucleoside HIV-1 reverse transcriptase inhibitors (3) are presented. Comparison of the structural and electronic properties with those of TIBO (1) and ...Nevirapine (2) yields a common three-dimensional model. This model permits the improvement of the lead compound 3 by chemical modification (5,6). Additionally, two new types of inhibitors (4, 7) with similar biological activity can be derived from this model. The structure of the new compounds, including their absolute configuration, are determined by X-ray crystallography.
The 3.0-A resolution x-ray structure of human des-Gla-coagulation factor Xa (fXa) has been determined in complex with the synthetic inhibitor DX-9065a. The binding geometry is characterized primarily ...by two interaction sites: the naphthamidine group is fixed in the S1 pocket by a typical salt bridge to Asp-189, while the pyrrolidine ring binds in the unique aryl-binding site (S4) of fXa. Unlike the large majority of inhibitor complexes with serine proteinases, Gly-216 (S3) does not contribute to hydrogen bond formation. In contrast to typical thrombin binding modes, the S2 site of fXa cannot be used by DX-9065a since it is blocked by Tyr-99, and the aryl-binding site (S4) of fXa is lined by carbonyl oxygen atoms that can accommodate positive charges. This has implications for natural substrate recognition as well as for drug design.
Background The explosive growth in the rate of X-ray determination of protein structures is fuelled largely by the expectation that structural information will be useful for pharmacological and ...biotechnological applications. For example, there have been intensive efforts to develop orally administrable antithrombotic drugs using information about the crystal structures of blood coagulation factors, including thrombin. Most of the low molecular weight thrombin inhibitors studied so far are based on arginine and benzamidine. We sought to expand the database of information on thrombin-inhibitor binding by studying new classes of inhibitors.
Results We report the structures of three new inhibitors complexed with thrombin, two based on 4-aminopyridine and one based on naphthamidine. We observe several geometry changes in the protein main chain and side chains which accompany inhibitor binding. The two inhibitors based on 4-aminopyridine bind in notably different ways: one forms a water-mediated hydrogen bond to the active site Ser195, the other induces a rotation of the Ser214–Trp215 peptide plane that is unprecedented in thrombin structures. These binding modes also differ in their ‘weak’ interactions, including CH–O hydrogen bonds and interactions between water molecules and aromatic
π-clouds. Induced-fit structural changes were also seen in the structure of the naphthamidine inhibitor complex.
Conclusions Protein flexibility and variable water structures are essential elements in protein–ligand interactions. Ligand design strategies that fail to take this into account may overlook or underestimate the potential of lead structures. Further, the significance of ‘weak’ interactions must be considered both in crystallographic refinement and in analysis of binding mechanisms.
We describe a new, efficient synthesis of DX‐9065a (4), a potent inhibitor of the blood coagulation enzyme factor Xa (fXa) which has previously been prepared in more than 20 steps. We saved ...approximately 10 steps starting with a Pd‐catalyzed cyanation of the triflate 10 of 7‐methoxynaphthalen‐2‐ol (9). After cleavage of the MeO group with boron tribromide, the triflate 6 was coupled to acrylate 5 in a Heck reaction (→3). The subsequent transformations led to DX‐9065 a.
Improved procedures for large scale preparation of oxy-substituted isoquinoiines are reported. Moreover, a simple and convenient protocol for alkaline work-up of titanium containing reaction mixtures ...is given, which is expected to be of general interest even for reactions on a technical scale.
Derivatives of (2-amidino-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)phenylacetic acid (TIPAC) were developed as inhibitors of factor Xa (fXa). The compounds are prepared using 15 synthetic steps on ...average. The most potent compounds (14, 17 , 22−26) display inhibition constants of K i = 21−55 nM but do not inhibit thrombin (K i = 5−>100 μM) and only weakly inhibit trypsin (K i = 0.08−5 μM). They bear a second basic moiety, e.g., substituted 1-(iminomethyl)piperidines, which is linked to C-4 of the phenyl group of TIPAC via an oxygen atom. The inhibition constants of these compounds are almost independent of the size of the (iminomethyl)piperidine substituent. Due to the fact that fXa displays two cation binding sites, namely, the S1 and S4 sites, in principle two binding modes are conceivable for the novel dibasic fXa inhibitors. Molecular modeling experiments based on the X-ray structures of uninhibited fXa and the DX-9065a/fXa complex were carried out. The results taken together with the inhibition constants clearly favor one binding mode: the tetrahydro-isoquinoline fills the S1 pocket even better than the naphthalene moiety of DX-9065a, and the (iminomethyl)piperidine residues occupy the S4 site.
Pyrroles from 1,2-Cyclopropanediamines and Aldehydes von der Saal, Wolfgang; Reinhardt, Robert; Stawitz, Josef ...
European journal of organic chemistry,
August 1998, Letnik:
1998, Številka:
8
Journal Article
Recenzirano
Mechanistic investigations by means of proton spectroscopy detected intermediates and uncovered the course of reactions in acetate‐buffered D4methanol of primary cyclopropanediamines cis‐ and ...trans‐2a with benzaldehyde (3a) or 2,2‐dimethylpropanal (3b), of secondary cyclopropanediamines cis‐ and trans‐2b with 3b, and of the ring‐methylated cyclopropanediamine trans‐14a and the aromatic aldehydes 3a and c. This study provided the basis of an expedient synthesis of pyrroles which takes place under exceptionally mild conditions. Irrespective of the configuration, primary (2a·2HBr) and secondary cyclopropanediammonium dibromides 2b and c·2HBr that are devoid of ring substituents react with aromatic aldehydes 3a, e–h, cinnamic aldehyde (3i), and 3b to afford 2‐substituted (8a, b) and 1,2‐disubstituted pyrroles (8c–i), respectively. The 3‐substituted secondary trans‐cyclopropanediammonium dibromides 24·2HBr furnish 1,2,4‐trisubstituted pyrroles 25. While the primary 1‐methylcyclopropanediammonium dibromide trans‐14a·2HBr reacts regioselectively with 3a and c to produce only 2,3‐substituted pyrroles 19a, c, the corresponding secondary dibromide trans‐14c·2HBr gives rise to the formation of mixtures of 1,2,3‐ (22) and 1,2,5‐trisubstituted pyrroles 23. The key step of pyrrole formation from 1,2‐cyclopropanediamines and aldehydes is the ring expansion of intermediate monoiminium ions of type 5 via azomethine ylides (E, Z)‐6 to yield dihydropyrrolium ions 7.
PDF
