Tyrosine kinases (TKs) play an important role in pathways that regulate cancer cell proliferation, apoptosis, angiogenesis and metastasis. Aberrant activity of TKs has been implicated in several types of cancers. In recent years, tyrosine kinase inhibitors (TKIs) have been developed to interfere with the activity of deregulated kinases. These TKIs are remarkably effective in the treatment of various human cancers including head and neck, gastric, prostate and breast cancer and several types of leukemia. However, these TKIs are transported out of the cell by ATP-binding cassette (ABC) transporters, resulting in development of a characteristic drug resistance phenotype in cancer patients. Interestingly, some of these TKIs also inhibit the ABC transporter mediated multi drug resistance (MDR) thereby; enhancing the efficacy of conventional chemotherapeutic drugs. This review discusses the clinically relevant TKIs and their interaction with ABC drug transporters in modulating MDR.

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Several studies have implicated the substantia nigra GABAergic system in the mediation of seizures in adult rats. The present study examines whether the different GABA receptors (GABAA and GABAB), are preferentially involved in this GABAergic seizure suppression mechanism. Adult rats were intranigrally infused with muscimol (GABAA receptor agonist), bicuculline (GABAA receptor antagonist) or baclofen (GABAB receptor agonist) and were exposed to flurothyl seizures. Results indicated that while infusions of muscimol had an anticonvulsant effect, infusions of bicuculline had a proconvulsant effect. Baclofen infusions were found to have no effect on seizures. These findings suggest an involvement of the nigral GABAA receptors in the mediation of seizures in adult rats.

On the basis of our previous findings, a series of 5-substituted 2-iminohydantoins has been synthesized and tested for anticonvulsant activity to better understand the SAR of 2-iminohydantoins. Among the compounds tested, (S)-(+)-1-carbobenzoxy-2-iminohydantoin analogs with ethyl (6)-, n-propyl (7a)-, isopropyl (8)-, allyl (9)-, and sec-butyl (11)-substituted groups at the C5 of the iminohydantoin ring provided the best activities against the MES test with ED50 values in the range of 52-74 mg/kg. All of the above compounds except 8 also showed activity against the scMET test with ED50 values in the range of 141-223 mg/kg. All significantly active compounds (1, 6, 7a, 8, 9, and 11) possessed aliphatic hydrocarbon side chains of two- to three-carbon lengths at the C5 position. All of the compounds with no or minimal activity had either shorter or longer side chains. The compounds substituted at the C5 position by aryl groups, arylalkyl groups, or alkyl and arylalkyl groups containing heteroatoms also showed no activity against the MES and scMET tests. The results suggested that the C5 side chain with the correct stereochemistry in 2-iminohydantoins provides optimal anticonvulsant activity when the side chains are aliphatic hydrocarbons with the length, ignoring branching, of two to three carbons.