Schiff base forming drugs: mechanisms of immune potentiation and therapeutic potential

Abstract

CD4 T-lymphocytes, which orchestrate immune responses, receive a cognitive signal when clonally distributed receptors are occupied by MHC class II bound peptides on antigen-presenting cells. The latter provide costimulatory or accessory signals through macromolecules such as B7.1 and B7.2 which interact with coreceptors on T-cells to regulate outcomes in terms of T-cell activation or specific non-responsiveness. Complementary studies at the chemical level have implicated Schiff base formation between specialised carbonyls and amines, constitutively expressed on antigen-presenting cell and T-cell surfaces, as an essential element in specific T-cell activation. The small xenobiotic Schiff base forming molecule tucaresol, which substitutes for the physiological donor of carbonyl groups to provide a costimulatory signal to CD4 T-helper lymphocytes (Th-cells), has been developed for testing as an immunopotentiatory drug. Tucaresol, which is orally bioavailable and systemically active, enhances CD4 Th-cell and CD8 cytotoxic T-cell responses in vivo and selectively favours a Th1-type profile of cytokine production. In murine models of virus infection and syngeneic tumour growth it has substantial therapeutic activity. Schiff base formation by tucaresol on T-cell surface amines provides a costimulatory signal to the T-cell through a mechanism that activates clofilium-sensitive K+ and Na+ transport. The signalling pathway utilised by tucaresol converges with T-cell receptor signalling at the level of MAP kinase, promoting the tyrosyl phosphorylation of ERK2 by MEK (mitogen-activated protein kinase kinase). The Schiff base forming class of immunopotentiatory drug provides the first orally active, mechanism-based immunopotentiatory agents for therapeutic testing. Tucaresol is currently undergoing pilot phase I/II clinical trials as an immunopotentiator in chronic hepatitis B virus infection, HIV infection and malignant melanoma.

<b>Studies on some VO(IV), Ni(II) and Cu(II) complexes of non-symmetrical tetradentate Schiff-bases</b>

“…Tucareso, a Schiff base-forming immunomodulator, is currently undergoing pilot phase I/II clinical trials as an immunopotentiator in chronic hepatitis B virus infection, HIV infection and malignant melanoma [7]. These ligands are widely studied because of their pronounced coordinating properties and stability [8][9].…”

“…These ligands are widely studied because of their pronounced coordinating properties and stability [8][9]. A number of symmetrical Schiff bases and chelates have been reported [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15], while comparatively little is known on synthesis and physico-chemical properties of asymmetric Schiff-base ligands and metal complexes [16][17][18][19][20]. Consequently, the aim of this work is to synthesize and characterize unsymmetrical Schiff-base ligands (derived from condensation of 1-phenyl-1,3-butanedione/2,4-pentanedione, ethylenediamine and 5-methoxy-2-hydroxy acetophenone) and their VO(IV), Ni(II) and Cu(II) complexes, in order to see the effect of the mixed π-electron ligand system and phenyl/methyl substituent on geometries and physico-chemical properties.…”

N-(3-{[(Z)-(3-Hydroxy-4-methylphenyl)imino]methyl}pyridin-2-yl)pivalamide

“…They have been used as model systems for biological macromolecules and have shown anticancer, antioxic, anti-inflammatory and antibacterial properties (Chen & Rhodes, 1996;Uhlenbrock et al, 1996;Anderson et al, 1997;Singh, 1999;Ambike et al, 2007). Schiff base compounds can be classified by their photochromic and thermochromic characteristics (Hadjoudis et al, 1987).…”

Schiff Bases Derived from 2-Hydroxynaphthalene-1-carbaldehyde and their Metal Complexes

“…2-Hydroxy-1-naphthaldehyde Schiff base that has the contributor framework, ON, ONO, N2O2 have been generally announced as the center for blend exceptionally foreign made ligands which discover route in numerous fields. There are numerous sensible purposes behind examiners significant consideration paid to Schiff bases formed from 2-hydroxynaphthalene-1-carbaldehyde that are possibly utilized as a part of variation natural fields [18,19], as models framework for organic molecules other than the natural activity [20,21]. The high fondness for the chelating of Schiff bases towards the progress metal is used in setting up their solid complexes [22,23].…”