Biological evaluation of 9-thioansamitocin P3.

Highly cytotoxic maytansine derivatives are widely used in targeted tumor delivery. Structure-activity studies published earlier suggested the C9 carbinol to be a key element necessary to retain the potency. However, in 1984 a patent was published by Takeda in which the synthesis of 9-thioansamitocyn (AP3SH) was described and its activity in xenograft models was shown.

The Suppressive Effect of Rebastinib on Triple-negative Breast Cancer Tumors Involves Multiple Mechanisms of Action.

Background/aim: High resistance of triple-negative breast cancer has prompted scientists to look for new targets susceptible to treatment. CDK16 has been suggested as a promising target whose inhibition can lead to tumor growth suppression. Rebastinib, a potent inhibitor of CDK16, has been reported to exhibit anti-tumor activity both in vitro and in vivo.

Search for Potent and Selective Aurora A Inhibitors Based on General Ser/Thr Kinase Pharmacophore Model.

Based on the data for compounds known from the literature to be active against various types of Ser/Thr kinases, a general pharmachophore model for these types of kinases was developed. The search for the molecules fitting to this pharmacophore among the ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against Ser/Thr kinases such as Aurora A, Aurora B and Haspin. Our work on the optimization of these molecules against Aurora A kinase allowed us to achieve several hits in a 3-5 nM range of activity with rather good selectivity and Absorption, Distribution, Metabolism, and Excretion (ADME) properties, and cytotoxicity against 16 cancer cell lines.

General Ser/Thr Kinases Pharmacophore Approach for Selective Kinase Inhibitors Search as Exemplified by Design of Potent and Selective Aurora A Inhibitors.

A general pharmachophore model for various types of Ser/Thr kinases was developed. Search for the molecules fitting to this pharmacophore among ASINEX proprietary library revealed a number of compounds, which were tested and appeared to possess some activity against several Ser/Thr kinases such as Aurora A, Aurora B and Haspin. The possibility of performing the fine-tuning of the general Ser/Thr pharmacophore to desired types of kinase to get active and selective inhibitors was exemplified by Aurora A kinase.

A re-examination of the MDM2/p53 interaction leads to revised design criteria for novel inhibitors.

The general model of epitope-type MDM2 inhibitor was developed based on the structural information on the complexes between MDM2 and various low molecular weight ligands found in the PDB database. Application of this model to our in-house library has led us to a new scaffold capable of interrupting protein-protein interactions. A synthetic library based on this and related scaffolds resulted in new classes of compounds that possess biochemical and cellular activity and good pharmacokinetic properties.

Determination of flomoxef in human plasma by liquid chromatography/electrospray ionization tandem mass spectrometry.

A specific, sensitive, rapid and reproducible method for the determination of flomoxef in human plasma using high-performance liquid chromatography-tandem mass spectrometry was developed and validated. Flomoxef was detected using an electrospay ionization method operated in negative-ion mode. Chromatographic separation was performed in gradient elution mode on a Luna® C18(2) column (3 μM, 20 × 4.

Oxygen-containing fragments in natural products.

An analysis of the chemical environment of the oxygen atoms in the DNP database compared to the CMC and SCD databases was performed. Some structural clusters were identified which are predominant among the natural products and can be considered as distinctive features of NPs. Fifty-three oxygen-containing structural fragments that are distinctive for the DNP (distinctive set of fragments DSF) in comparison with the SCD have been identified.

Propenylamide and propenylsulfonamide cephalosporins as a novel class of anti-MRSA beta-lactams.

Novel C(3) propenylamide and propenylsulfonamide cephalosporins have been synthesized and tested for their ability to inhibit the penicillin-binding protein 2' (PBP2') from Staphylococcus epidermidis and the growth of a panel of clinically relevant bacterial species, including methicillin-resistant Staphylococcus aureus (MRSA). The most potent compounds inhibited the growth of MRSA strains with minimum inhibitory concentrations (MIC) as low as 1 microg/mL. The structure-activity relationship revealed the potential for further optimization of this new cephalosporin class.

Potent, orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors.

Two structurally distinct series of SCD (Delta9 desaturase) inhibitors (1 and 2) have been previously reported by our group. In the present work, we merged the structural features of the two series. This led to the discovery of compound 5b (CVT-12,012) which is highly potent in a human cell-based (HEPG2) SCD assay (IC(50)=6nM).

Orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors.

We discovered a structurally novel SCD (Delta9 desaturase) inhibitor 4a (CVT-11,563) that has 119 nM potency in a human cell-based (HEPG2) SCD assay and selectivity against Delta5 and Delta6 desaturases. This compound has 90% oral bioavailability (rat) and excellent plasma exposure (dAUC 935 ng h/mL). Additionally, 4a shows moderately selective liver distribution (three times vs plasma and adipose tissue) and relatively low brain penetration.

Novel, potent, selective, and metabolically stable stearoyl-CoA desaturase (SCD) inhibitors.

We identified a series of structurally novel SCD (Delta9 desaturase) inhibitors via high-throughput screening and follow-up SAR studies. Modification of the central bicyclic scaffold has proven key to our potency optimization effort. The most potent analog (8g) had IC(50) value of 50 pM in a HEPG2 SCD assay and has been shown to be metabolically stable and selective against Delta5 and Delta6 desaturases.

Efficient synthesis of 5-substituted 2-aryl-6-cyanoindolizines via nucleophilic substitution reactions.

2-Aryl-6-cyano-7-methyl-5-indolizinones were successfully converted into 2-aryl-5-chloro-6-cyano-7-methylindolizines. The obtained 5-chloroindolizines readily underwent nucleophilic substitution at position 5 leading in high yields to novel 5-functionalised indolizines.

Examination of the 1,4-disubstituted azetidinone ring system as a template for combretastatin A-4 conformationally restricted analogue design.

A series of novel 1,4-diaryl-2-azetidinones was prepared by stereospecific Staudinger reaction as conformationally restricted analogues of combretastatin A-4 because molecular modeling studies suggested close geometric similarities. They were evaluated for cytotoxicity against a number of human tumor and normal cell lines. Strong potencies were observed, with the best compounds exhibiting IC(50)'s of 25-74 nM against human neuroblastoma IMR 32 cell growth and a variety of other cell lines.

Abilities of 3,4-diarylfuran-2-one analogs of combretastatin A-4 to inhibit both proliferation of tumor cell lines and growth of relevant tumors in nude mice.

Background: Combretastatin A-4 (CA-4) and its analogs are potent inhibitors of tubulin polymerization and display strong inhibitory activity on both solid tumor and tumor cell growth. Since natural CA-4 is difficult to synthesize and also isomerizes to an inactive form quite readily, a recently reported new 3,4-diarylfuran-2-one-based series of CA-4 analogs was investigated, in the hope of bypassing some of these difficulties. These analogs appear to offer a valuable tool for CA-4 research because of their extremely facile synthesis from readily available starting materials.

An adjustable release rate linking strategy for cytotoxin-peptide conjugates.

Peptide hormones are often rapidly internalized after binding to and activation of their receptors which are sometimes over-expressed on tumor cells. Thus, peptide ligands are increasingly being utilized for specific tumor cell targeting and internalization of radioactive isotopes for tumor imaging and for specifically delivering and internalizing cytotoxic moieties. Here, we describe a new carbamate linker system containing a series of built-in nucleophile assisted releasing (BINAR) groups which enable the 'fine-tuning' of intracellular cleavage rates of free cytotoxic agents containing reactive OH groups.