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  1. Awang N, Kamaludin NF, Ghazali AR
    Pak J Biol Sci, 2011 Aug 01;14(15):768-74.
    PMID: 22303582
    Cancer is one of the main causes of mortality and morbidity in world. New compounds are currently being synthesized to combat this disease. The organotins are gaining more attention as anti-cancer agents due to their potent cytotoxicity properties. In this study, a series of newly synthesized organotins namely dimethyltin (IV) (compound 1), dibutyltin (IV) (compound 2) and triphenyltin (IV) benzylisopropyldithiocarbamate (compound 3) were assessed for their cytotoxic activities against human Chang liver cells and hepatocarcinoma HepG2 cells. The cytotoxicity of these organotins in both cells upon 24 h treatment was assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Compound 2 and 3 exhibited potent cytotoxic activities towards both cells where the IC50 values were less then 10 microM. The IC50 value for compound 2 was 2.5 microM in Chang liver cells and 7.0 microM in HepG2 cells whereas compound 3 exhibited an IC50 value of 1.5 microM in Chang liver cells and 2.5 microM in HepG2 cells. Therefore, compound 2 and 3 were more toxic against human Chang liver cells as compared to hepatocarcinoma HepG2 cells. Interestingly, compound 1 did not have any IC50 value in both cells and hence can be classified as non-toxic. In conclusion, organotin (IV) benzylisopropyldithiocarbamate with insertion of dibutyl and triphenyl functional group possess potent cytotoxicity properties. Structural modification of these compounds can be carried out in further studies to produce less or non toxic effects towards normal human cell.
  2. Haezam FN, Awang N, Kamaludin NF, Mohamad R
    Saudi J Biol Sci, 2021 May;28(5):3160-3168.
    PMID: 34025187 DOI: 10.1016/j.sjbs.2021.02.060
    Context: Diphenyltin(IV) diallyldithiocarbamate compound (Compound 1) and triphenyltin(IV) diallyldithiocarbamate compound (Compound 2) are two newly synthesised compounds of organotin(IV) with diallyldithiocarbamate ligands.

    Objective: To assess the cytotoxic effects of two synthesised compounds against HT-29 human colon adenocarcinoma cells and human CCD-18Co normal colon cells.

    Materials and methods: Two successfully synthesised compounds were characterised using elemental (carbon, hydrogen, nitrogen, and sulphur) analysis, Fourier-Transform Infrared (FTIR), and 1H, 13C 119Sn Nucleus Magnetic Resonance (NMR) spectroscopies. The single-crystal structure of both compounds was determined by X-ray single-crystal analysis. The cytotoxicity of the compounds was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazholium bromide (MTT) assay upon 24 h of treatment. While the mode of cell death was determined based on the externalisation of phosphatidylserine using a flow cytometer.

    Results: The elemental analysis data of the two compounds showed an agreement with the suggested formula of (C6H5)2Sn[S2CN(C3H5)2]2 for Compound 1 and (C6H5)3Sn[S2CN(C3H5)2] for Compound 2. The two major peaks of infrared absorbance, i.e., ν(C = N) and ν(C = S) were detected at the range of 1475-1479 cm-1 and 972-977 cm-1, respectively. The chemical shift of carbon in NCS2 group for Compound 1 and 2 were found at 200.82 and 197.79 ppm. The crystal structure of Compound 1 showed that it is six coordinated and crystallised in monoclinic, P21/c space group. While the crystal structure of Compound 2 is five coordinated and crystallised in monoclinic, P21/c space group. The cytotoxicity (IC50) of the two compounds against HT-29 cell were 2.36 μM and 0.39 μM. Meanwhile, the percentage of cell death modes between 60% and 75% for compound 1 and compound 2 were mainly due to apoptosis, suggesting that both compounds induced growth arrest.

    Conclusion: Our study concluded that the synthesised compounds showed potent cytotoxicity towards HT-29 cell, with the triphenyltin(IV) compound showing the highest effect compared to diphenyltin(IV).

  3. Syed Annuar SN, Kamaludin NF, Awang N, Chan KM
    Front Chem, 2021;9:657599.
    PMID: 34368075 DOI: 10.3389/fchem.2021.657599
    Organotin(IV) compounds have wide applications in industrial and agricultural fields owing to their ability to act as poly(vinyl chloride) stabilizers and catalytic agents as well as their medicinal properties. Moreover, organotin(IV) compounds may have applications as antitumor, anti-inflammatory, antifungal, or antimicrobial agents based on the observation of synergistic effects following the binding of their respective ligands, resulting in the enhancement of their biological activities. In this review, we describe the antiproliferative activities of organotin(IV) compounds in various human cancer cell lines based on different types of ligands. We also discuss the molecular mechanisms through which organotin(IV) compounds induce cell death via apoptosis through the mitochondrial intrinsic pathway. Finally, we present the mechanisms of cell cycle arrest induced by organotin(IV) compounds. Our report provides a basis for studies of the antitumor activities of organotin(IV) compounds and highlights the potential applications of these compounds as anticancer metallodrugs with low toxicity and few side effects.
  4. Kamaludin NF, Awang N, Baba I, Hamid A, Meng CK
    Pak J Biol Sci, 2013 Jan 01;16(1):12-21.
    PMID: 24199481
    Organotin complexes are recognized as the biologically active compounds in inducing cancerous cells death at very low doses. To date, organotin compounds currently appear among the most potent candidates in research related to the new anticancer drugs. In this study, new organotin(IV) N-butyl-N-phenyldithiocarbamate compounds have been successfully synthesized between the reaction of N-butylaniline amine with organotin(IV) chloride in 1:2/1:1 molar ratio. All compounds were characterized using the elemental analysis, FT-IR and NMR spectroscopy. The single crystal structure was determined by X-ray single crystal analysis. The elemental analysis showed good agreement with the suggested formula (C4H9)2Sn[S2CN(C4H9)(C6H5)]2 (Compound 1 and 2), (C6H5)2Sn[S2CN(C4H9)(C6H5)]2 (Compound 3) and (C6H5)3Sn[S2CN(C4H9)(C6H5)] (Compound 4). The important infrared absorbance peaks, v (C = N) and v(C = S) were detected in range between 1457-1489 cm(-1) and 951-996 cm(-1), respectively. The chemical shift of carbon in NCS2 group obtained from 13C NMR was found in range 198.86-203.53 ppm. The crystal structure of compound 4 showed that the dithiocarbamate ligand coordinates in a monodentate fashion. It crystallized in monoclinic P2(1)/n space group with the crystal cell parameter: a = 10.0488(1) angstroms, b = 18.0008(2) angstroms, c = 15.2054(2) angstroms, beta = 102.442(1) degrees and R = 0.044. The cytotoxicity (IC50) of these compounds against Jurkat E6.1 and K-562 leukemia cells were in the range between 0.4-0.8 and 1.8-5.3 microM, respectively as assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazholium bromide (MTT) assay. In conclusion, our study demonstrate that all compounds showed potent cytotoxicity towards both cell lines tested with the triphenyltin(IV) compound displayed the greatest effect.
  5. Awang N, Kamaludin NF, Hamid A, Mokhtar NW, Rajab NF
    Pak J Biol Sci, 2012 Sep 01;15(17):833-8.
    PMID: 24163967
    Studies on the discovery of new cancer treatment by using metal-based compounds such as tin (Sn) has now greatly being synthesized and evaluated to identify their effectiveness and suitability to be developed as a new anticancer drug.

    APPROACH: This study was carried out to evaluate the cytotoxicity of triphenyltin(lV) methylisopropyldithiocarbamate (compound 1) and triphenyltin(IV) ethylisopropyldithiocarbamate (compound (2) on chronic myelogenus leukemia cells. The determination of their cytotoxicity (IC50) at different time of exposure and concentration was carried out through the employment of 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay.

    RESULTS: The IC50 values obtained for compound 1 and 2 following treatment at 24, 48 and 72 h were 0.660, 0.223, 0.370 microM and 0.677, 0.306, 0.360 microM, respectively. Cell morphological changes such as apoptotic and necrotic features were also been observed.

    CONCLUSION: The compounds tested were found to give cytotoxic effect against chronic myelogenus leukemia (K-562) cell at a micromolar dose. Thus, further study on their specific mechanism of actions in the human cells should be carried out to elucidate their potential as an anticancer agent.

  6. Mohamad R, Awang N, Kamaludin NF, Jotani MM, Tiekink ER
    Acta Crystallogr E Crystallogr Commun, 2017 Feb 01;73(Pt 2):260-265.
    PMID: 28217355 DOI: 10.1107/S2056989017001098
    The complete mol-ecule of the title compound, [Sn(C4H9)2(C5H10NOS2)2], is generated by a crystallographic mirror plane, with the SnIV atom and the two inner methyl-ene C atoms of the butyl ligands lying on the mirror plane; statistical disorder is noted in the two terminal ethyl groups, which deviate from mirror symmetry. The di-thio-carbamate ligand coordinates to the metal atom in an asymmetric mode with the resulting C2S4 donor set defining a skew trapezoidal bipyramidal geometry; the n-butyl groups are disposed to lie over the longer Sn-S bonds. Supra-molecular chains aligned along the a-axis direction and sustained by methyl-ene-C-H⋯S(weakly coordinating) inter-actions feature in the mol-ecular packing. A Hirshfeld surface analysis reveals the dominance of H⋯H contacts in the crystal.
  7. Mohamad R, Awang N, Kamaludin NF, Jotani MM, Tiekink ERT
    Acta Crystallogr E Crystallogr Commun, 2018 Mar 01;74(Pt 3):302-308.
    PMID: 29765711 DOI: 10.1107/S2056989018001901
    The crystal and mol-ecular structures of the two title organotin di-thio-carbamate compounds, [Sn(C4H9)2(C7H14NO2S2)2], (I), and [Sn(C6H5)3(C5H10NOS2)], (II), are described. Both structures feature asymmetrically bound di-thio-carbamate ligands leading to a skew-trapezoidal bipyramidal geometry for the metal atom in (I) and a distorted tetra-hedral geometry in (II). The complete mol-ecule of (I) is generated by a crystallographic twofold axis (Sn site symmetry 2). In the crystal of (I), mol-ecules self-assemble into a supra-molecular array parallel to (10-1) via methyl-ene-C-H⋯O(meth-oxy) inter-actions. In the crystal of (II), supra-molecular dimers are formed via pairs of weak phenyl-C-H⋯π(phen-yl) contacts. In each of (I) and (II), the specified assemblies connect into a three-dimensional architecture without directional inter-actions between them. Hirshfeld surface analyses confirm the importance of H⋯H contacts in the mol-ecular packing of each of (I) and (II), and in the case of (I), highlight the importance of short meth-oxy-H⋯H(but-yl) contacts between layers.
  8. Mohamad R, Awang N, Kamaludin NF, Jotani MM, Tiekink ER
    Acta Crystallogr E Crystallogr Commun, 2016 Oct 1;72(Pt 10):1480-1487.
    PMID: 27746946
    The crystal and mol-ecular structures of two tri-phenyl-tin di-thio-carbamates, [Sn(C6H5)3(C16H16NS2)], (I), and [Sn(C6H5)3(C7H14NO2S2)], (II), are described. In (I), the di-thio-carbamate ligand coordinates the Sn(IV) atom in an asymmetric manner, leading to a highly distorted trigonal-bipyramidal coordination geometry defined by a C3S2 donor set with the weakly bound S atom approximately trans to one of the ipso-C atoms. A similar structure is found in (II), but the di-thio-carbamate ligand coordinates in an even more asymmetric fashion. The packing in (I) features supra-molecular chains along the c axis sustained by C-H⋯π inter-actions; chains pack with no directional inter-actions between them. In (II), supra-molecular layers are formed, similarly sustained by C-H⋯π inter-actions; these stack along the b axis. An analysis of the Hirshfeld surfaces for (I) and (II) confirms the presence of the C-H⋯π inter-actions but also reveals the overall dominance of H⋯H contacts in the respective crystals.
  9. Abd Aziz NA, Awang N, Kamaludin NF, Anuar NNM, Hamid A, Chan KM, et al.
    Anticancer Agents Med Chem, 2024;24(12):942-953.
    PMID: 38629375 DOI: 10.2174/0118715206309421240402093335
    BACKGROUND: Organotin(IV) complexes of dithiocarbamate are vital in medicinal chemistry, exhibiting potential in targeting cancer cells due to their unique properties that enhance targeted delivery. This study aimed to synthesize and characterize organotin(IV) N-ethyl-N-benzyldithiocarbamate complexes (ONBDCs) and evaluate their cytotoxicity against A549 cells, which are commonly used as a model for human lung cancer research.

    METHODS: The two ONBDC derivatives - ONBDC 1 (dimethyltin(IV) N-ethyl-N-benzyldithiocarbamate) and ONBDC 2 (triphenyltin(IV) N-ethyl-N-benzyldithiocarbamate) - were synthesized via the reaction of tin(IV) chloride with N-ethylbenzylamine in the presence of carbon disulfide. A range of analytical techniques, including elemental analysis, IR spectroscopy, NMR spectroscopy, UV-Vis spectrometry, TGA/DTA analysis, and X-ray crystallography, was conducted to characterize these compounds comprehensively. The cytotoxic effects of ONBDCs against A549 cells were evaluated using MTT assay.

    RESULTS: Both compounds were synthesized and characterized successfully via elemental and spectroscopies analysis. MTT assay revealed that ONBDC 2 demonstrated remarkable cytotoxicity towards A549 cells, with an IC50 value of 0.52 μM. Additionally, ONBDC 2 displayed significantly higher cytotoxic activity against the A549 cell line when compared to the commercially available chemotherapeutic agent cisplatin (IC50: 32 μM).

    CONCLUSION: Thus, it was shown that ONBDC 2 could have important anticancer properties and should be further explored as a top contender for creating improved and specialized cancer treatments.

  10. Mohamad R, Awang N, Kamaludin NF, Jotani MM, Tiekink ERT
    Acta Crystallogr E Crystallogr Commun, 2018 May 01;74(Pt 5):630-637.
    PMID: 29850080 DOI: 10.1107/S2056989018005133
    The crystal and mol-ecular structures of two tri-phenyl-tin di-thio-carbamate compounds, viz. [Sn(C6H5)3(C8H16NS2)], (I), and [Sn(C6H5)3(C10H12NS2)], (II), are described. The di-thio-carbamate ligand in each mol-ecule coordinates in an asymmetric fashion resulting in heavily distorted tetra-hedral C3S coordin-ation geometries for the Sn atoms, with the distortions traced to the close approach of the non-coordinating thione-S atom. The mol-ecular packing in both compounds features C-H⋯π(Sn-phen-yl) inter-actions. In (I), the donors are Sn-phenyl-C-H groups leading to centrosymmetric aggregates, while in (II), the donors are both Sn-phenyl-C-H and methyl-C-H groups leading to supra-molecular chains propagating along the b axis. The identified aggregates assemble into their respective crystals with no directional inter-actions between them. An analysis of the Hirshfeld surfaces show distinctive patterns, but an overwhelming predominance (>99% in each case) of H⋯H, C⋯H/H⋯C and S⋯H/H⋯S contacts on the respective Hirshfeld surface.
  11. Haezam FN, Awang N, Kamaludin NF, Jotani MM, Tiekink ERT
    Acta Crystallogr E Crystallogr Commun, 2020 Feb 01;76(Pt 2):167-176.
    PMID: 32071741 DOI: 10.1107/S2056989020000122
    The crystal and mol-ecular structures of the title organotin di-thio-carbamate compounds, [Sn(C6H5)3(C7H10NS2)] (I) and [Sn(C6H5)2(C7H10NS2)2] (II), present very distinct tin atom coordination geometries. In (I), the di-thio-carbamate ligand is asymmetrically coordinating with the resulting C3S2 donor set defining a coordination geometry inter-mediate between square-pyramidal and trigonal-bipyramidal. In (II), two independent mol-ecules comprise the asymmetric unit, which differ in the conformations of the allyl substituents and in the relative orientations of the tin-bound phenyl rings. The di-thio-carbamate ligands in (II) coordinate in an asymmetric mode but the Sn-S bonds are more symmetric than observed in (I). The resulting C2S4 donor set approximates an octa-hedral coordination geometry with a cis-disposition of the ipso-carbon atoms and with the more tightly bound sulfur atoms approximately trans. The only directional inter-molecular contacts in the crystals of (I) and (II) are of the type phenyl-C-H⋯π(phen-yl) and vinyl-idene-C-H⋯π(phen-yl), respectively, with each leading to a supra-molecular chain propagating along the a-axis direction. The calculated Hirshfeld surfaces emphasize the importance of H⋯H contacts in the crystal of (I), i.e. contributing 62.2% to the overall surface. The only other two significant contacts also involve hydrogen, i.e. C⋯H/H⋯C (28.4%) and S⋯H/H⋯S (8.6%). Similar observations pertain to the individual mol-ecules of (II), which are clearly distinguishable in their surface contacts, with H⋯H being clearly dominant (59.9 and 64.9%, respectively) along with C⋯H/H⋯C (24.3 and 20.1%) and S⋯H/H⋯S (14.4 and 13.6%) contacts. The calculations of energies of inter-action suggest dispersive forces make a significant contribution to the stabilization of the crystals. The exception is for the C-H⋯π contacts in (II) where, in addition to the dispersive contribution, significant contributions are made by the electrostatic forces.
  12. Haezam FN, Awang N, Kamaludin NF, Jotani MM, Tiekink ERT
    Acta Crystallogr E Crystallogr Commun, 2019 Oct 01;75(Pt 10):1479-1485.
    PMID: 31636979 DOI: 10.1107/S2056989019012490
    The crystal and mol-ecular structures of the title triorganotin di-thio-carbamate, [Sn(C6H5)3(C7H14NS2)], are described. The mol-ecular geometry about the metal atom is highly distorted being based on a C3S tetra-hedron as the di-thio-carbamate ligand is asymmetrically chelating to the tin centre. The close approach of the second thione-S atom [Sn⋯S = 2.9264 (4) Å] is largely responsible for the distortion. The mol-ecular packing is almost devoid of directional inter-actions with only weak phenyl-C-H⋯C(phen-yl) inter-actions, leading to centrosymmetric dimeric aggregates, being noted. An analysis of the calculated Hirshfeld surface points to the significance of H⋯H contacts, which contribute 66.6% of all contacts to the surface, with C⋯H/H⋯C [26.8%] and S⋯H/H⋯H [6.6%] contacts making up the balance.
  13. Abd Aziz NA, Awang N, Chan KM, Kamaludin NF, Mohamad Anuar NN
    Molecules, 2023 Aug 03;28(15).
    PMID: 37570810 DOI: 10.3390/molecules28155841
    Organotin (IV) dithiocarbamate has recently received attention as a therapeutic agent among organotin (IV) compounds. The individual properties of the organotin (IV) and dithiocarbamate moieties in the hybrid complex form a synergy of action that stimulates increased biological activity. Organotin (IV) components have been shown to play a crucial role in cytotoxicity. The biological effects of organotin compounds are believed to be influenced by the number of Sn-C bonds and the number and nature of alkyl or aryl substituents within the organotin structure. Ligands target and react with molecules while preventing unwanted changes in the biomolecules. Organotin (IV) dithiocarbamate compounds have also been shown to have a broad range of cellular, biochemical, and molecular effects, with their toxicity largely determined by their structure. Continuing the investigation of the cytotoxicity of organotin (IV) dithiocarbamates, this mini-review delves into the appropriate method for synthesis and discusses the elemental and spectroscopic analyses and potential cytotoxic effects of these compounds from articles published since 2010.
  14. Kamaludin NF, Kamarulzaman F, Abdullah R, Chan KM, Inayat-Hussain SH
    Genes Environ, 2023 Dec 11;45(1):34.
    PMID: 38072940 DOI: 10.1186/s41021-023-00290-5
    The Malaysian Society of Toxicology (MySOT), founded in 2010, emerged as a response to the growing need for a collective and interdisciplinary effort to study the effects of substances on human health, and the environment. By fostering collaboration between toxicologists, researchers, regulators, industry experts, and various relevant subject matter experts, MySOT has played a vital role in generating knowledge and promoting safety to safeguard both human and environmental well-being. Within the 13 years since its establishment, MySOT has made substantial progress in the advancement of toxicology in Malaysia. Over the years, MySOT has supported many initiatives, including organizing conferences, seminars, and workshops in which experts from various fields present their research, discuss emerging trends, and propose strategies to reduce toxic substance exposure risk. The society has also been actively involved in the broader landscape of toxicology research and policy influence in Malaysia. MySOT shoulders the responsibility of conveying accurate information and educating the public about health risks associated with toxic substances. Therefore, the society aims to collaborate with governmental organizations, professional bodies, and international toxicology organizations to share ideas, resources, and expertise. MySOT seeks to gather toxicological experts in the region and significantly contribute to a safer and healthier community, therefore supporting the United Nations Sustainable Development Goals (SDGs), by being actively involved with all of its stakeholders, both local and international.
  15. Razali NSC, Lam KW, Rajab NF, Jamal ARA, Kamaludin NF, Chan KM
    Genes Environ, 2024 Feb 01;46(1):4.
    PMID: 38303058 DOI: 10.1186/s41021-023-00297-y
    BACKGROUND: Previously, we have reported on the two curcuminoid analogues with piperidone derivatives, namely FLDP-5 and FLDP-8 have more potent anti-proliferative and anti-migration effects than curcumin. In this study, we further investigated the mode of cell death and the mechanism involved in the cell death process induced by these analogues on human glioblastoma LN-18 cells.

    RESULTS: The FLDP-5 and FLDP-8 curcuminoid analogues induced LN-18 cell death through apoptosis in a concentration-dependent manner following 24 h of treatment. These analogues induced apoptosis in LN-18 cells through significant loss of mitochondrial mass and mitochondrial membrane potential (MMP) as early as 1-hour of treatment. Interestingly, N-acetyl-l-cysteine (NAC) pretreatment did not abolish the apoptosis induced by these analogues, further confirming the cell death process is independent of ROS. However, the apoptosis induced by the analogues is caspases-dependent, whereby pan-caspase pretreatment inhibited the curcuminoid analogues-induced apoptosis. The apoptotic cell death progressed with the activation of both caspase-8 and caspase-9, which eventually led to the activation of caspase-3, as confirmed by immunoblotting. Moreover, the existing over-expression of miRNA-21 in LN-18 cells was suppressed following treatment with both analogues, which suggested the down-regulation of the miRNA-21 facilitates the cell death process.

    CONCLUSION: The FLDP-5 and FLDP-8 curcuminoid analogues downregulate the miRNA-21 expression and induce extrinsic and intrinsic apoptotic pathways in LN-18 cells.

  16. Nadzir MSM, Lin CY, Khan MF, Latif MT, Dominick D, Hamid HHA, et al.
    Environ Sci Pollut Res Int, 2017 Jun;24(18):15278-15290.
    PMID: 28500553 DOI: 10.1007/s11356-017-9131-1
    Open biomass burning in Peninsula Malaysia, Sumatra, and parts of the Indochinese region is a major source of transboundary haze pollution in the Southeast Asia. To study the influence of haze on rainwater chemistry, a short-term investigation was carried out during the occurrence of a severe haze episode from March to April 2014. Rainwater samples were collected after a prolonged drought and analyzed for heavy metals and major ion concentrations using inductively coupled plasma mass spectroscopy (ICP-MS) and ion chromatography (IC), respectively. The chemical composition and morphology of the solid particulates suspended in rainwater were examined using a scanning electron microscope coupled with energy-dispersive X-ray spectroscopy (SEM-EDS). The dataset was further interpreted using enrichment factors (EF), statistical analysis, and a back trajectory (BT) model to find the possible sources of the particulates and pollutants. The results show a drop in rainwater pH from near neutral (pH 6.54) to acidic (
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