Yosu Vara

Tandem [8 + 2] cycloaddition--[2 + 6 + 2] dehydrogenation reactions involving imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines.

The reaction between benzynes and imidazo[1,2-a]pyridines (pyrimidines) to form benzo[a]imidazo[5,1,2-cd]indolizines and 2,3,9c-triazocyclopenta[j,k]fluorenes has been studied computationally and experimentally. It is found that these reactions take place via tandem [(pi)8(s) + (pi)2(s)] and [(sigma)2(s) + (pi)6(s) + (sigma)2(s)] processes. The [8 + 2] cycloaddition steps are essentially barrierless, and the aromatization steps occur via highly synchronous aromatic transition structures. From an experimental standpoint, the reaction is feasible under microwave irradiation and using 2-(trimethylsilyl)phenyl triflates as benzyne precursors. Depending on the substitution pattern in the starting triflate a complete regiocontrol of the reaction can be achieved. The tetracyclic compounds thus prepared emitted blue light when excited at 365 nm and exhibited interesting photophysical properties.

Regioselective Preparation of Benzo[b]furans from Phenols and α-Bromoketones

In this paper, a fully regiocontrolled synthesis of either 2- and 3-substituted benzo[b]furans is described. Direct reaction between phenols and α-bromoacetophenones in the presence of neutral alumina yields 2-substituted benzo[b]furans with complete regiocontrol. When a basic salt such as potassium carbonate is used, the corresponding 2-oxoether is obtained. Cyclization of these latter compounds promoted by neutral alumina yields the corresponding 3-substituted benzo[b]furans. Using the former method, Moracin M and other analogues can be obtained from commercial sources in two preparative steps. DFT calculations provide reasonable reaction paths to understand the formation of 2-substituted benzo[b]furans.

Formation of γ-oxoacids and 1H-pyrrol-2(5H)-ones from α,β-unsaturated ketones and ethyl nitroacetate.

Michael addition of ethyl nitroacetate on α,β-unsaturated ketones followed by Nef oxidation under hydrolytic conditions yields γ-oxoacids instead of the corresponding α,δ-dioxoesters. A concerted decarboxylation step is proposed on the basis of computational results. Finally, conversion of the γ-ketoacids thus prepared into 1H-pyrrol-2(5H)-ones by reaction with primary amines under Paal-Knorr conditions is also reported.

Trans-stereoselectivity in the reaction between homophthalic anhydride and imines.

The reaction between homophthalic anhydride and imines in the presence of TiCl4 and diisopropyl ethyl amine is trans-selective. Under these conditions, the reaction using homochiral imines can be highly diastereoselective, thus allowing the synthesis of enantiopure 1,2,3,4-tetrahydro-1-oxoquinoline-4-carboxylic acids.

Design, Synthesis, and Functional Evaluation of Leukocyte Function Associated Antigen-1 Antagonists in Early and Late Stages of Cancer Development

The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its α(L)-chain inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report the structure-based design, small-scale synthesis, and biological activity evaluation of a novel family of LFA-1 antagonists. The design led to the synthesis of a family of highly substituted homochiral pyrrolidines with antiproliferative and antimetastatic activity in a murine model of colon carcinoma, as well as potent antiadhesive properties in several cancer cell lines in the low micromolar range. NMR analysis of their binding to the isolated I-domain shows that they bind to the I-domain allosteric site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled.

Synthesis of 11C-labeled Kendine 91, a histone deacetylase inhibitor

In the present paper, the synthesis of (11)C-labeled Kendine 91 (a HDAC inhibitor which has shown in vitro and in vivo activity in HCT 116 and MOLT 4 human cancer cell lines) is described for the first time. The radiosynthesis has been approached by reaction of the non-radioactive precursor 6-((3-(4-hydroxyphenyl)-5-phenyl-1H-pyrrole-2-carboxamide))hexanehydroxamic acid with [(11)C]CH(3)I in basic media. Despite the presence of more than one reactive site in the chemical structure of the precursor, acceptable radiochemical yield (8.2±2.1%, decay corrected to the end of bombardment), specific activity (28.2±9.4 GBq/μmol) and radiochemical purity values (>95%) were obtained in reasonably short preparation times (~40 min). Despite the moderate radiochemical yield, final radioactivity and radioactivity concentration values (1.8±0.3 GBq and 180 MBq/ml, respectively) should be sufficient for putative in vivo studies in animals.

In vitro and in vivo activity of a new small-molecule inhibitor of HDAC6 in mantle cell lymphoma

Cancer origin and development is associated not only with genetic alterations, but also with the disturbance of epigenetic profiles.[1][1] In this regard, the tumoral epigenome is characterized by both specific and general shifts in the DNA methylation and histone-modification landscapes.[1][1]

Development and validation of a LC‐MS assay for the quantification of ikh12 a novel anti‐tumor candidate in rat plasma and tissues and its application in a pharmacokinetic study

IKH12 is a novel histone deacetylase 6 selective inhibitor. A rapid and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for the quantification of IKH12 in rat plasma and tissue with kendine 91 as internal standard (IS). The samples were prepared by liquid-liquid extraction with tert-butyl methyl ether. The chromatographic separation was accomplished by using a Zorbax Extend C18 4.6 × 150 mm, 5 µm column, with a mobile phase consisting of methanol and 0.1% formic acid (75:25 v/v). Multiple reaction monitoring, using electrospray ionization in positive ion mode, was employed to quantitatively detect IKH12 and IS. The monitored transitions were set at m/z 418 → 252 and 444 → 169 for IKH12 and kendine 91, respectively. The calibration curve was linear over the concentration range 2-1000 ng mL(-1) . The intra- and inter-assay precision and accuracy of the quality controls and the limit of quantification were satisfactory in all cases (according to European Medicines Agency guidelines). Stability studies showed that plasma samples were stable in the chromatography rack for 24 h and at -80°C for 2 months and also after three freeze-thaw cycles. This method was successfully applied to a pharmacokinetic study of IKH12 in rat.

Abstract C46: Design, synthesis, and functional evaluation of leukocyte-function associated antigen-1 (LFA-1) antagonists in early and late stages of cancer development.

The integrin leukocyte function associated antigen 1 (LFA-1) binds the intercellular adhesion molecule 1 (ICAM-1) by its αL-chain inserted domain (I-domain). This interaction plays a key role in cancer and other diseases. We report the structure-based design, small-scale synthesis, and biological activity evaluation of a novel family of LFA-1 antagonists. The design led to the synthesis of a family of highly substituted homochiral pyrrolidines with antiproliferative and antimetastatic activity in a murine model of colon carcinoma, as well as potent antiadhesive properties in several cancer cell lines in the low micromolar range. NMR analysis of their binding to the isolated I-domain shows that they bind to the I-domain allosteric site (IDAS), the binding site of other allosteric LFA-1 inhibitors. These results provide evidence of the potential therapeutic value of a new set of LFA-1 inhibitors, whose further development is facilitated by a synthetic strategy that is versatile and fully stereocontrolled.