Toxicity and anti-tumour activity of organotin (IV) compounds

Organotins are widely described as anti-tumor, anti-inflammatory, anti-fungal, and antimicrobial agents. In addition to their uses in biomedical fields, organotins are also used in agricultural and industrial applications. These materials are more toxic than inorganic cans, which are poorly absorbed and are excreted on the surface of the can, and cause toxicity to a variety of organisms and damage the environment. This review focuses on organotin’s toxicity and uses in biomedical fields.


INTRODUCTION
In the last few decades, organotin complexes have played a vital role due to their structural and therapeutic activities. Although organotin compounds have attracted great attention in treating cancer, such as their therapeutic use on numerous tumor cells, little is known regarding their action mechanisms. Structures, and biological actions of organotin(IV) compounds have lately been plotted. 1 Organotin carboxylates are often used because they have cytotoxic and biocidal potential, in addition to their agriculture and industrial applications. Generally, the coordination number and molecular structures of the tin atom are the main important aspect to specify the biocidal activity of organotin (IV) complexes. These parameters are essential in understanding their relation to the nature of tin element bonds with its coordination sphere of tin atoms. 2 Chemical and biological factors effect characterizing tin compounds' toxicity. Several studies discussed the progressions of several kinds of bacteria that can be repressed via organotin derivatives that are associated with membrane functions and their influence on solute transport, energy conservation transport and substrate oxidation. There is limited information regarding the toxic effects of organotin compounds on microorganisms such as fungi and algae. Their impact is recognized on mitochondria stems and chloroplasts mainly from higher plants as well as animal systems. The tri-organotin compounds cause action as opposed to mitochondria and chloroplasts leading to tumors. Another key point, that di-organotin compounds seems to work through binding to dithiol functional group on cofactors and enzymes, while ionophores work against ATPase. Furthermore, DNA does not show negative effects due to concentration. However, understanding the biochemical reactions of tin compounds is still under the study by many researchers as no effects were found on microbial enzymes. 3 Organic tin (IV) complexes have been synthesized and characterized in recent years, as they have shown important biological activities. The activities of these complexes were evaluated on a variety of cancer cells as well as in some other applications such as lubricants, coatings, catalysts, polymers, and organic synthesis. 4 Previously, several studies have been conducted about the interaction between benzohydroxamic acid and its derivatives and di-organotin (IV) acceptors. Despite their synergistic effects, several of this type of compounds have demonstrated remarkable activity in vitro against a various human tumor cell. 5 It has been reported that a small number of cancers are primarily caused by viruses. 6 Thus, an anticancer drug might be an antiviral agent although the converse is not necessarily true. The protein and nucleic acid moieties of viruses are operator chelating agents and the goal of the metallotherapeutic designer to alter the virus by metal chelation, which will therefore lessened by the viral activity. 7

QSAR OF ORGANOTINS
The toxicity of tri-substituted (R3Sn's) and alkyl are more than that of di-substituted substituent of organotins (R2Sn's). On the other hand, mono-substituted organotins (RSn's) have lower toxicity when compared to others. However, organotins are converted to be toxic when tetra-substituted organotins (R4Sn's) metabolized to tri-substituted organotins (R3Sn's). Tri-substituted alkyl compounds of chains contain 3, 4, 5 carbon atoms or phenyl-, and cyclohexyl organotin compounds are usually the very poisonous to microorganisms. The total molecular surface area of the tin compound and the ratio between n-octanol and water (Kow) also are responsible for identifying the toxicity of tri-substituted tin compounds that refer to the relation between hydrophilicity (water soluble) and lipophilicity (fat soluble) substances, if Kow is less than one indicates substance more soluble in water and less toxic and if it is greater than one that means more hydrophobic and predicts high toxicity.

ORGANOTIN AS ANTI-TUMOR AGENT
Recent studies have been conducted that low amounts of organic tin inhibit the growth of tumors. Many researchers urged the work of the genetic pathway in cancer cells, to open new research horizons about the organic tin compound.
In this review the testing of the yields of organotin compounds in vivo and in vitro was illustrated. Studying organotin compounds gives way to new horizons for the potential prosperity of anti-tumor drug industry. When the early studies of anti-tumor with cis-platin ( Figure 1) revealed to have a remarkable effect against leukemia L1210 and sarcoma 180 in mice. The compound has been approved for clinical use and it has continued to be used for medical purposes. The trans-isomer in Figure 1 showed its limited activity against tumors, either because of their chemical or biological limitations. 8

Figure 1 The platinum complex (A) Cis-platin, (B) Trans-platin.
Over the last five decades there has been considerable interest in the organometallic field which is a branch of chemistry that links the organic and inorganic fields. Since the discovery of organometallic compounds in the 1980s, these compounds have been proved to be useful catalysts for extensive industrial applications such as antiknock additives for gasoline and biocides. 9 Furthermore, the wide medicinal usage area of titanium dichloride provoked great interest in research into organometallic compounds as anti-tumor agents because of their structure being related to cis-platin and its derivatives.
Organometallic-based compounds possessing anti-tumor activities can be classified into three fundamental classes: metallocene diacido deriviatives, ferricenium salt, and diorganotin complexes as shown in Figure 2 that displays the structural formulas of the complexes classes. 10,11 Iron(III) ion in ferrocinium salts has two cyclopentadienyl coordination bonds at a sandwich formation. These compounds are hydrophilic due to their high stability in water which can prevent the growth of various types of tumors, and they are potentially valuable for clinical use because of their powerful oxidizing characteristics and their low toxicity and exceptional water solubility. 12 Bi-organic (IV) complexes comprise a class of potential anti-tumor agents, which have been effective against P388 lymphocytic leukemia and MCF-7 breast tumor.
Hydroxy acids such as arylhydroxamic acid are biologically active due to their high ability to donate oxygen. Previously, scientists studied the interactions between benzohydroxamic acid and di-organotin(IV) acceptors and its derivatives, with the synergistic effect of those compounds, they found that most of the di-organotin (IV) derivatives showed remarkable activity against a sequence of diverse cancer cells in humans. The study also demonstrated that the complexes of benzohydroxamic acid, diethyltin (IV) and dibutyltin (IV) are predicted to be leading materials. The studies about organotin(IV) compounds anti-tumor activities date as far back as 1929 (U S Patent 1930) and a key development in the field of bio organotin chemistry in the last two decades to find that organotin compounds have the potential to be used as anticarcinogenic, [13][14][15] and also as fungicides, biocides and pesticides. 16 Tetrahedral, trigonal bi-pyramidal and octahedral are most common geometries of tin(IV) complexes. Addition of neutral organic donor ligands may raise the coordination number of tin atom from four to five or six. 17 The organotin derivatives containing ligands with O, N or S donor atoms may coordinate to the tin to make the Sn-N, Sn-O or Sn-S bonds which have a potential to play an essential factor in their activity against the tumor cells, the mechanism of action has not yet been known. One of the most important organic ligands containing two oxygen atoms are hydroxamic acids and have the potential to interact with organotin(IV) compounds may generate complexes with different geometric structures and features to make them biologically active. 18 Recently, studies about the biological mechanisms of these complexes have failed to add data on this issue. 19,20 However, only scanty and scattered information are available on the specific anti-carcenogenic activities of organotin(IV) unsubstituted mono-and dihydroxamates 21,22 but N-substituted hydroxamic acids have not been studied yet properly.
Organotin hydroxamates derivatives were discovered in 1984, 23 but their application as a anti-tumor agent was not recognized until 1991. They have been used against normal and preneoplastic rat hepatocytes. The preneoplastic hepatocytes were found to be obviously sensitive to organotin hydroxamtes, whereas the normal hepatocytes were less sensitive. In addition to this a series of dibutyltin(IV) complexes of unsubstituted arylhydroxamic acids have been used on human A-549 tumour cells and P388 leukaemia 22 and the results illustrate that nearly all compounds exhibit significant activity against human A-549 tumor cells and showing a significant difference in the activity of the same compounds against A-549 and P388.
Several naturally occurring acids and the synthesis of a number of medicinally active hydroxylamine derivatives has been reported in recent years while some of the hydroxamic acids have already found applications in drug-delivery system 24,25 in iron-solubilisation and transport 26 and in DNA cleavage. [27][28][29] Studies regarding antitumour applications of the organotin are still not enough to have complete understanding of the mechanism. It is established that the drug molecules goes through a series of procedures such as crossing of cell-membrane,chemical hydrolysis, transfer in the physiological intermediate, and subsequently arrive at the close of goal DNA molecule and figure active intermediates R2Sn2+ which may have direct interaction with the phosphate group of DNA structures, invoking cancer cells via damaging the DNA, which leads to cell-death. The molecular structure of organotin complexes which are consistent with the two-pole complementary standard, 30 usually present two types of alkyl groups one leaving (R') and the other is the remaining (R) group which is stable in an aqueous solution. The organic ligand R can go through the lipid bilayers and reach closer to the target molecules and the binding modes flanked by the ligand R' and tin undergo the mechanism of hydrolysis in the physiological medium. Therefore, a successful application may require the drug molecules to possess a suitable partition coefficient and suitable bulk size of hydrophobic groups. 22

CONCLUSIONS
The main aim of this review was to demonstrate the toxicity of organotin IV derivatives and its application in biomedical field as anti-tumor agent. Different studies have been done on organotin(IV) compound but still much efforts need to be done on this aspect to evaluate and found the specific uses in biochemical area. It can be concluded from this study that organotin(IV) compounds have a significant uses in medical fields as T-cells inhibitor by chelate with specific complexes that have the ability to form cis-platin moieties.

ABBREVIATIONS
ATPas, adenosinetriphosphatase; DNA, deoxyribonucleic acid; Pt, platinum; RSn, Alkyl group mono-substituted; R2Sn, Alkyl group disubstituted; R3Sn, Alkyl group tri substi-Abdualbasit M. Graisa holds a master's degree from the University of Liverpool and has worked as a researcher for years at UKM University in Malaysia to conduct many scientific articles in the medical field of organic tin complexes.
Khalid Zainulabdeen , in 2021, holds Ph.D. in Polymer Chemistry from the University of Wollongong in Australia. His M.Sc. degree in Biochemistry was received in 2004 from the University of Al-Nahrain. He has several years of experience as a researcher in biochemistry and hydrogels and as a lecturer at Al-Nahrain University.
Israa Salman she received her M.Sc. in Biotechnology from Al-Nahrain University in 2007. In 2020, she got Ph.D. from the University of Manchester. She is working as a lecturer at the College of Science at Al-Nahrain University and has many research in her field.