Synthesis And Biological Activities Of As(?)-containing Schiff Bases And Acridines

Arsenic-based medicine, as the oldest drug in the world, was first used by Chinese and Greek healers more than2,000years ago. Up to now, arsenicals are still remained in prescription of some traditional Chinese medicines as key ingredients. Especially in recent three decades, Chinese scholars have obtained resounding success at curing acute promyelocytic leukaemia by arsenic trioxide. It reignites enthusiasm and interest of the people concerned on arsenic-based medicine. Arsenic is a metalloid at fourth period and VA group in the periodic table. Most of arsenicals show high toxicities and bioactivities. It conduces to comprehend and expound biological effects and mechanisms of action of arsenic to carry out research for toxicity, toxicology and biological activity of arsenicals. This study could contribute to enhance advantage and avoid disadvantage of arsenic in the utilization of arsenical as drugs to serve human people better. China is an arsenic-rich country and proved arsenic reserves in China ranks the first in the worldwide. It is very important that arsenic reserves in our country could be developed and utilized strictly, efficiently and scientifically. The biological effects of arsenic should be studied extensively and in depth for the purpose of reducing harm caused by human's exposure to arsenic and repairing and protecting environment.There are much more literatures about arsenic exposure and environmental effect of arsenic than about arsenic-based dugs especially about arsenic-based tumor drugs to be reported in recent years. The literatures about arsenic-based tumor drugs were focused on research for inorganic arsenical arsenic trioxide. But, the literatures about organoarsenicals as tumor drugs are not very many. Organoarsenicals are a class of organometalloid compounds with As-C bond. Organic arsenicals have lower toxicity, lower net content of arsenic element and better membrane permeability than inorganic arsenicals. Structural design and modification of organoarsenicals used for drugs are more feasible than inorganic arsenicals. A series of As(?)-containing Schiff bases and acridines were designed and synthesized in this paper. The inhibitory activity of the synthetic organoarseniccals against E. coli and Monilia albican were studied. Antiproliferative activity against human lung adenocarcinoma cell line A549was researched. Arsenicals show their potent toxicities and bioactivities mainly by inhibiting activities of some key enzymes. Therefore, binding reactions between synthetic organoarseniccals with serum albumin were also studied. This paper is divided into the following five parts:In chapter1, occurring and distribution of arsenic in nature, history of arsenic as medicine, successful case of arsenic as drug in the treatment of acute promyelocytic leukaemia, and biological effects and mechanism of action of arsenic were described. Advancement about organoarsenicals as antibacterial and antitumor agents was reviewed. The ideas of subject study and innovative results were also presented at the end of this chapter.In chapter2, a series of As(III)-containing Schiff bases and acridines were designed and synthesized from nontoxic, inexpensive and available starting material arsanilic acid. The formation of As-C bonds and transformation of As(V) to As(?) were carried out by experimental methods. Convenient synthetic methods of As(III)-containing Schiff bases and acridines were estlished. The structures and properties of target molecules were characterized by m.p. test, elemental analysis, IR, MS,'HNMR,13CNMR. High yields were obtained via controlling conditions of solvent, catalyst, time and temperature of synthetic reactions.In chapter3, the antibacterial activities of As(III)-containing Schiff bases and acridine on E.coli (CCTCC AB91112), E.coli (ATCC25922) and Monilia albican (ATCC64550) were investigated by microcalorimetry. The experimental result showed the arsenic(III)-containing Schiff bases2a?2b?2c?2d?2e?3a?4a and acridine5a at micro molar concentration exhibit strong antibacterial activities. Most of the arsenicals display the feature of considerable lag phase inhibition on the cells growth. The results proved that As(III) had higher toxicity on prokaryotic cell than As(V) and inorganic arsenicals had higher toxicity on prokaryotic cell than organic arsenicals.In chapter4, cytotoxicity tests shown that synthetic organo metalloids displayed significant antitumor bioactivity in vitro against human lung adenocarcinoma A549cell line. The potent cytotoxic effects on the tumor cells of the organo metalloids were observed in accordance with dose-response mode. In the nonlinear fitting of Inc against viability in%, compounds2b and3a follow exponential decay first order function to display higher dose sensitivity in lower range of concentration having the lowest IC50of0.176?M and0.202?M respectively and the highest activity among them. And the others follow Boltzmann function. Staining of monolayer cells and fluorescence imaging studies suggest that the organoarsenicals are mitochondria-targeted antiproliferative agents to dysfunction mitochondria causing apoptosis and necrosis of tumor cells.In chapter5, in order to understand cytotoxicities and action mechanism of the organoarsenicals at the molecular level, the binding reactions between synthetic organoarsenicals small molecules and serum albumin biomacromolecules were studied by methods of fluorescence, ultraviolet and circular dichroism spectra as well as molecular modeling study. The research has shown that the organoarsenical caused a static quenching of the intrinsic fluorescence of serum albumin by the formation of complex at ground state between them. Structural feature of the synthetic organoarsenicals lies in bearing hydrophobic aromatic rings at which there are some acceptors and donors of hydrogen bonds. All of results have a good match with the structural feature of the molecules. The binding site of the small molecules locate at Sudlow's Site I in domain A of serum albumin biomacromolecules under concentration of stoichiometric ratio of1:1. Resulting binding constant is about1x104-5to present binding and transporting abilities at high side of average level in the reversible binding reaction. Negative values of AG and AH of binding reactions have shown that the reactions were thermodynamic favorable and spontaneous processes driven by enthalpy. Negative value of AS of binding reactions between SPAO and HSA as well as BIPA and BSA are entropy-decreasing processes while positive value of AS of binding reactions between OAPA and HSA is an entropy-increasing process. The entropy-decreasing processes result from the increase of hydration of amino acid residues in which native H-bond network was damaged by binding interaction between organoarsenicals and proteins. This interaction contributed to negative change of enthalpy (AH<0) and negative change of entropy (AS<0). The entropy-increasing processes result mainly from unfolding of polypeptide chains causing by binding interaction between them. This process driven by entropy made disorder increase. The binding reaction changed the conformations of the serum albumin which lead to loss of activities and dysfunction of the protein. The fact could contribute to understanding at molecular level high toxicities or high bioactivities of arsenic by exerting potent inhibition on key enzymes.