Design, Synthesis, and Biological Evaluation of a Series of Lavendustin A Analogues That Inhibit EGFR and Syk Tyrosine Kinases, as Well as Tubulin Polymerization

Abstract

A series of N-alkylamide analogues of the lavendustin A pharmacophore were synthesized and tested for inhibition of the epidermal growth factor receptor (EGFR) protein tyrosine kinase and the nonreceptor protein tyrosine kinase Syk. Although several compounds in the series were effective inhibitors of both kinases, it seemed questionable whether their inhibitory effects on these kinases were responsible for the cytotoxic properties observed in a variety of human cancer cell cultures. Accordingly, a COMPARE analysis of the cytotoxicity profile of the most cytotoxic member of the series was performed, and the results indicated that its cytotoxicity profile was similar to that of antitubulin agents. This mechanism of action was supported by demonstrating that most compounds in the series were moderately effective as inhibitors of tubulin polymerization. This suggests that the lavendustin A analogues reported here, as well as some of the previously reported lavendustin A analogues, may be acting as cytotoxic agents by a mechanism involving the inhibition of tubulin polymerization.

Anilinodialkoxyquinazolines: Screening Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Potential Tumor Imaging Probes

“…Iodine-125 labeled 11d (specific activity 583-596 Ci/mmol) was employed as the radioligand 36 and non-specific binding was determined by adding 11c, the bromo-analog, to the assay. EGFR binding values, expressed as an IC 50 , are shown in Table 2. All of the compounds demonstrated high affinity for the receptor with IC 50 s ranging from 0.4 -51 nM.…”

Two Distinct Conformations of GABA Locked by Embedding in the Bicyclo[3.1.0]hexane Core Structure

“…Oxidative removal of the PMB group using cerium ammonium nitrate in CH 3 CN/H 2 O [26] (50 % yield) and acid hydrolysis of the ester yielded the free amino acid hydrochloride 11 (48 % yield), which, upon reaction with Boc anhydride, was transformed into the final Boc-protected rac-(1S,2S,5R,6S)-2-aminobicyclo[2.1.0]hexane-6-carboxylic acid 7 b in 80 % yield. [27] Diminished yields in the oxidation/hydrolysis steps may be attributed to the lower stability of these bicycles in acidic media, especially in the presence of protic solvents. [28] [23] For structures with significantly puckered five-membered ring units (q 1 > 108), the upper branch (boat-shaped structures) contains 232 cases, whereas the lower branch (chair-type structures) contains 19 cases.…”

Palladium‐Catalyzed Synthesis of Functional Tetralins via Benzylic Activation

“…in DMF (5 mL) at 110 8C. After 2 more hours at 110 8C, the mixture was cooled to room temperature and hydrolyzed with a saturated aqueous solution of NH 4 Cl. After extraction with CH 2 Cl 2 , the combined organic extracts were washed with brine, dried over MgSO 4 , filtered and concentrated under reduced pressure.…”

“…The tetralin moiety is found in materials [1] and polymer chemistry, [2] and functional tetralin derivatives are also useful intermediates to access biologically active natural compounds and analogues. Thus, such a structure is present in hamigeran B, a strong antiviral and low cytotoxic compound, [3] a lavendustin A analogue, which exhibits tubulin polymerization inhibition, [4] the s-receptor (+)-pentazoine, [5] the highly potent and selective IP agonist FK 788, [6] inhibitors of human placental aromatase, [7] and prolyl endopeptidase (PEP). [8] Several methods are used for the preparation of the tetralin motif.…”