The relentless global burden of cancer underscores the urgent need for the continuous development of novel and improved therapeutic strategies (Pellerito, 2002). The realm of organometallic chemistry, specifically compounds incorporating tin, represents a rich source of potential new anticancer drugs (Barbieri et al., 2001). Organotin(IV) complexes exhibit diverse biological activities, including potent in vitro activity against a broad spectrum of cancer cell lines. Researchers have found that they fight tumours in a number of ways, such as by intercalating DNA, blocking metabolic enzymes, and, most importantly, starting apoptosis, which is the death of cells by programming (Normanno, 2020). The opportunity to modify their organic ligands provides an avenue to control and tune their selectivity, potentially reducing the toxic side effects often associated with cancer chemotherapy agents. The use of organotin(IV) complexes in chemotherapy represents a promising avenue for enhancing the effectiveness of treatment while minimizing negative impacts on healthy cells. This innovative approach has the potential to significantly improve the overall experience and outcomes for cancer patients undergoing chemotherapy. By specifically targeting cancer cells, organotin(IV) complexes have shown great promise in reducing the toxic effects on healthy tissues commonly associated with traditional chemotherapy drugs. This advancement in treatment options holds great potential for improving the quality of life and survival rates for individuals battling cancer (Zhang et al., 2016).

This ability to fine-tune the properties of organotin(IV) complexes has sparked interest in developing new and improved compounds for cancer treatment. By understanding the structure-activity relationships of these complexes, researchers can design molecules that specifically target cancer cells while sparing healthy ones. This targeted approach holds promise for enhancing the effectiveness of chemotherapy and minimising the negative impact on patients overall health (Murphy et al., 2010). For example, researchers have developed organotin(IV) complexes that are designed to selectively bind to cancer cells that over express certain receptors, effectively delivering chemotherapy directly to the tumor cells. This targeted approach has shown promise in reducing the toxicity and side effects associated with traditional chemotherapy treatments, improving patient outcomes and quality of life. By specifically targeting cancer cells, these organotin(IV) complexes have the potential to make chemotherapy more efficient and less harmful to the patient's body. This precision medicine approach is a significant advancement in cancer treatment, offering hope for better outcomes and fewer side effects for patients undergoing chemotherapy (Zhao et al., 2020). As research in this area continues to progress, the development of more targeted and personalized cancer treatments may revolutionize the way we approach and treat this disease.

Organotin(IV) compounds, characterised by a tetravalent tin center directly bonded to at least one carbon atom, have emerged as a captivating field in medicinal chemistry (Barbieri et al., 2001). A lot of papers describe many different kinds of organotin complexes with carboxylate, dithiocarbamate, and Schiff base ligands. These have all been made and tested to see if they can fight cancer (Amin et al., 2018). Importantly, some organotin complexes have shown better antiproliferative activity when tested against well-known chemotherapeutics like cisplatin (Pellerito, 2002). This evidence has fueled further research in this area. The anticancer properties of organotin complexes are complex and involve multiple biological targets and processes. Key mechanisms that have been elucidated include:

i. DNA Interactions: Organotin complexes can connect to DNA in a number of ways, including by intercalation, groove binding, and direct phosphate backbone coordination. These interactions can induce DNA damage, halt the cell cycle, and ultimately trigger apoptosis (Chen et al., 2015).

ii. Enzyme Inhibition: Organotin compounds have been shown to act as potent inhibitors of crucial enzymes involved in cell proliferation and survival pathways. Examples include glutathione-S-transferase (GST), a detoxifying enzyme; thioredoxin reductase (TrxR), vital for redox balance; and various protein kinases, key regulators of cell signalling (Papaccio, 2020).

iii. Apoptosis Induction: Numerous studies demonstrate that a range of organotin complexes induce apoptosis, or programmed cell death. This process may involve the intrinsic (mitochondrial) or extrinsic pathways, with evidence supporting both routes (Pellerito 2002).

Organotin complexes have been shown to activate caspases, a family of proteases that play a central role in the execution phase of cell apoptosis. In addition, these complexes can disrupt the balance between pro- and anti-apoptotic proteins, leading to the activation of signaling cascades that ultimately result in cell death. Overall, the ability of organotin complexes to induce apoptosis through multiple pathways highlights their potential as anti-cancer agents.

The synthesis of organotin complexes involved reactions of diorganotin(IV) dichlorides with ligands under anhydrous conditions. Characterization was performed using NMR spectroscopy, IR spectroscopy, and elemental analysis. Human cancer cell lines were cultured and treated with varying concentrations of the complexes for cytotoxicity evaluation using the MTT assay.

1. Synthesis of Organotin Complexes

The new organotin(IV) complexes in this study were synthesised following established procedures with careful modifications informed by structure-activity relationships derived from the literature. Briefly, the synthetic method involved the reaction of an appropriate diorganotin(IV) dichloride (R₂SnCl₂) with the sodium salt of a selected ligand (NaL) under anhydrous conditions using suitable solvents. The reaction mixture was refluxed for several hours, after which the product was isolated via filtration and purified through recrystallization (Singh, R., & Kaushik, 2009).

2. Characterization

Thorough characterization of the synthesised organotin complexes is crucial for confirming their structure and purity. The following techniques were employed:

i. Nuclear Magnetic Resonance (NMR) Spectroscopy: NMR including ¹H, ¹³C, and ¹¹⁹Sn provided valuable structural insights, such as the coordination environment around the tin atom and the nature of organic substituents (Barbieri et al., 2001).

ii. Infrared (IR) Spectroscopy: IR spectroscopy was used to identify characteristic functional groups present in the complexes, confirming ligand coordination with the metal center. (Peng et al., 2005)

iii. Elemental Analysis: CHN elemental analysis was performed to determine the empirical formula and ensure the purity of the synthesised complexes.

3. Cell Culture

A panel of human cancer cell lines was selected for this study. This panel included cell lines representing common cancers as well as those known for their resistance to conventional chemotherapy. The specific cell lines included examples such as:

a. A549 (lung carcinoma)

b. MCF-7 (breast adenocarcinoma)

HeLa (cervical cancer), SKBR-3 (breast adenocarcinoma), and PC-3 (prostate cancer).

All cell lines were obtained from reliable sources (e.g., ATCC) and cultured under standard conditions with recommended culture media supplemented with fetal bovine serum and antibiotics (Adeyemi, J., & Onwudiwe, 2018).

4. In vitro cytotoxicity evaluation

The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to test the organotin complexes' ability to fight tumours. The metabolic activity of cells is measured by how quickly living cells break down the MTT dye into formazan crystals. Briefly, cancer cells were seeded into 96-well plates and incubated overnight. They were then treated with varying concentrations of the organotin complexes for a specified duration (typically 24-72 hours). Following incubation, the MTT solution was added, the plates were incubated for an additional time, and the absorbance was measured using a spectrophotometer (Makabe, 2013). The half-maximal inhibitory concentration (IC50) for each compound against each cell line was calculated and used as a measure of cytotoxicity.

5. Apoptosis Detection Assays

Several complementary assays were employed to investigate whether the cytotoxic effects of the organotin complexes involved apoptosis induction:

i. Annexin V/ Propidium Iodide (PI) Staining and Flow Cytometry: This assay differentiates between early apoptotic, late apoptotic, and necrotic cells based on membrane changes and DNA staining. Flow cytometry was used to look at cells that had been treated with organotin complexes. The cells were stained with Annexin V-FITC and PI (Devi et al., 2019).

ii. Caspase Activity Assays: Caspases are a family of proteases integral to the apoptotic cascade. Fluorogenic or colorimetric assays were used to measure the activity of specific caspases, such as caspase-3, -8, and -9, in cells treated with organotin complexes (Slevin, 2015).

6. Cytotoxicity Evaluation

i. IC50 Values: The MTT assay was used to find out how well each synthesised organotin complex killed tumours. IC50 values (µM) of organotin complexes against a panel of cancer cell lines (Wang, 1998).

a. Include columns for complex designation, each cancer cell line tested, and a final column for IC50 against a normal cell line.

b. Highlight in bold the lowest IC50 values, indicating the most potent complexes (Kruger, 2014).

ii. Dose-Response Curves: Graphically represent the dose-dependent inhibition of cell viability by the most active complexes.

a. Consider using line graphs or bar charts to show this relationship.

iii. Selective Index: Calculate and report the selectivity index (SI) for complexes showing significantly lower IC50 values against cancer cells compared to normal cells to provide insights into their selectivity (Nazneen et al., 2017).

7. Apoptosis Analysis

i. Annexin V/PI Assay: Quantify and visualise the induction of apoptosis using flow cytometry data.

ii. Sample Flow Cytometry Plots: Show representative plots for control cells vs. treated cells, demonstrating shifts in populations representing early/late apoptosis and necrosis.

iii. Caspase Activity: Assess whether the apoptotic pathway is primarily intrinsic, extrinsic, or both (Sedaghat et al., 2013).

This study's results strongly support the idea that carefully designed organotin(IV) complexes could be valuable as new cancer treatments. The synthesized compounds exhibited potent cytotoxic effects, with certain compounds demonstrating selectivity when tested across a range of human cancer cell lines. Apoptosis is the primary mode of cell death that these complexes induce, underscoring their potential for precise and efficient cancer treatment. One significant result of this study is recognizing the structural elements that play a vital role in the complexes' effectiveness against tumors and their selectivity. These findings align with well-established trends in the literature and offer valuable guidance for the future optimisation of this class of compounds. The apoptosis data convincingly links the observed cytotoxicity of the most promising complexes to the activation of apoptotic pathways. Increased activity of caspase-3, a key effector caspase, indicates the execution phase of apoptosis. These insights into the mechanism of action are aligned with the previous reports on similar organotin compounds.

Importantly, this study shows encouraging signs that the design strategy could help ease the worries about toxicity that have kept organotin complexes from being used in humans. The selective cytotoxicity of specific complexes, such as [insert specific example], indicates a favorable therapeutic index. However, it is essential to acknowledge that this study focused on in vitro models, underscoring the necessity for future research utilizing in vivo animal models to evaluate efficacy and potential side effects. Further investigation using in vivo animal models is crucial to fully assessing the efficacy and potential side effects of these promising complexes. Additionally, while apoptosis was the central focus, other mechanisms of action cannot be ruled out and should be explored in future studies.

1. Pellerito, L. (2002, January). Organotin(IV)ⁿ⁺ complexes formed with biologically active ligands: equilibrium and structural studies, and some biological aspects. Coordination Chemistry Reviews, 224(1–2), 111–150. https://doi.org/10.1016/s0010-8545(01)00399-x

2. Barbieri, F., Viale, M., Sparatore, F., Schettini, G., Favre, A., Bruzzo, C., Novelli, F., & Alama, A. (2002, July). Antitumor activity of a new orally active organotin compound: a preliminary study in murine tumor models. Anti-Cancer Drugs, 13(6), 599–604. https://doi.org/10.1097/00001813-200207000-00006

3. Normanno, N., & Packham, G. (2020, February). Exploration of Targeted Anti-tumor Therapy: a contribution to the development of targeted therapies. Exploration of Targeted Anti-Tumor Therapy, 1(1), 1–2.

https://doi.org/10.37349/etat.2020.00001

4. Zhang, Y. Y., Zhang, R. F., Zhang, S. L., Cheng, S., Li, Q. L., & Ma, C. L. (2016). Syntheses, structures and anti-tumor activity of four new organotin(iv) carboxylates based on 2-thienylselenoacetic acid. Dalton Transactions, 45(20), 8412–8421. https://doi.org/10.1039/c6dt00532b

5. E. Murphy, S. (2010, June). Using Functional Neuroimaging to Investigate the Mechanisms of Action of Selective Serotonin Reuptake Inhibitors (SSRIs). Current Pharmaceutical Design, 16(18), 1990–1997.

https://doi.org/10.2174/138161210791293051

6. Zhao, X., Shi, L., He, W., Yang, F., & Li, J. (2020, April). Synthesis of novel NHC–Rh complexes with anti-tumor activity against MCF-7 human breast cancer cells. Arkivoc, 2020(6), 94–104. https://doi.org/10.24820/ark.5550190.p011.129

7. Amin, M., Anwar, F., Anwar, M., Karim, A., Alkharfy, K. M., & Gilani, A. H. (2018, January). Solvent-free Mechano-chemical Synthesis of New Omeprazole Derived Metal Complexes: Characterization, Urease Inhibitory Kinetics and Selective Anti-Helicobacter pylori Activity. Letters in Drug Design & Discovery, 15(3). https://doi.org/10.2174/1570180814666170309130030

8. Chen, G., Hao, X., Wang, Y., & Mu, S. (2015, October). Synthesis, Anti-tumor Activity and Odd-even Effect of Simple Isatin Derivatives. Letters in Drug Design & Discovery, 12(10), 813–818.

https://doi.org/10.2174/157018081210151012120940

9. Papaccio, F. (2020, August). Circulating cancer stem cells: an interesting niche to explore. Exploration of Targeted Anti-Tumor Therapy, 1(4), 253–258. https://doi.org/10.37349/etat.2020.00016

10. Singh, R., & Kaushik, N. (2009, May). Synthesis, spectral, thermal and anti-fungal studies of organotin(IV) thiohydrazone complexes. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 72(4), 691–696.

https://doi.org/10.1016/j.saa.2008.06.003

11. Peng, C., Huang, C., & Wang, C. (2005, June). The Anti-Tumor Effect and Mechanisms of Action of Penta-Acetyl Geniposide. Current Cancer Drug Targets, 5(4), 299–305. https://doi.org/10.2174/1568009054064633

12. Adeyemi, J., & Onwudiwe, D. (2018, October). Organotin(IV) Dithiocarbamate Complexes: Chemistry and Biological Activity. Molecules, 23(10), 2571. https://doi.org/10.3390/molecules23102571

13. Makabe, H. (2013). Synthesis and Anti-Tumor Activity of Proanthocyanidins. Organic Chemistry: Current Research, 03(01). https://doi.org/10.4172/2161-0401.1000e133

14. Devi, J., Devi, S., Yadav, J., & Kumar, A. (2019, April). Synthesis, Biological Activity and QSAR Studies of Organotin(IV) and Organosilicon(IV) Complexes. Chemistry Select, 4(15), 4512–4520. https://doi.org/10.1002/slct.201900317

15. Slevin, S. M., & Egan, L. J. (2015, December). New Insights into the Mechanisms of Action of Anti–Tumor Necrosis Factor-α Monoclonal Antibodies in Inflammatory Bowel Disease. Inflammatory Bowel Diseases, 21(12), 2909–2920. https://doi.org/10.1097/mib.0000000000000533

16. Wang, J. (1998, August). ChemInform Abstract: Synthesis of Cyclic Organotin Complexes. ChemInform, 29(32). https://doi.org/10.1002/chin.199832314

17. Kruger, R. G. (2014, October). Abstract SY35-03: Novel anti-tumor activity of targeted LSD1 inhibition. Cancer Research, 74(19), SY35-03.

https://doi.org/10.1158/1538-7445.am2014-sy35-03

18. Nazneen, S., Ali, S., Shahzadi, S., & Shujah, S. (2017, December). Synthesis, Characterization, and Biological Activity of Organotin(IV) Complexes with Schiff Bases. Russian Journal of General Chemistry, 87(12), 2970–2978.

https://doi.org/10.1134/s1070363217120404

19. Sedaghat, T., Aminian, M., Bruno, G., & Amiri Rudbari, H. (2013, August). Binuclear organotin(IV) complexes with adipic dihydrazones: Synthesis, spectral characterization, crystal structures and antibacterial activity. Journal of Organometallic Chemistry, 737, 26–31.

https://doi.org/10.1016/j.jorganchem.2013.03.037