Chiral metallic anticancer drugs: A brief-review European Journal of Chemistry 13 (4) (2022) 483-490 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2022 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. https://dx.doi.org/10.5155/eurjchem.13.4.483-490.2312 European Journal of Chemistry View Journal Online View Article Online Chiral metallic anticancer drugs: A brief-review Sofi Danish Mukhtar 1 and Mohammad Suhail 2,* 1 Department of Chemistry, Government Degree College Ganderbal, Jammu & Kashmir-191201, India 2 Department of Chemistry, Siddhartha Degree College, Aakhlaur Kheri (Saharanpur), Uttar Pradesh-251311, India * Corresponding author at: Department of Chemistry, Siddhartha Degree College, Aakhlaur Kheri (Saharanpur), Uttar Pradesh-251311, India. e-mail: suhailchem.786@gmail.com (M. Suhail). 10.5155/eurjchem.13.4.483-490.2312 Received: 20 July 2022 Received in revised form: 10 September 2022 Accepted: 19 September 2022 Published online: 31 December 2022 Printed: 31 December 2022 Chiral metallic drugs are becoming the hottest point of discussion in the field of medicinal chemistry. As we know that more than 80% drugs are chiral in nature, and prescribed in the racemic form. The main problem with chiral drugs is the different biological activities of different enantiomers. This is because the human body has a chiral environment, as there is the presence of protein, carbohydrates, enzymes, and other chiral macromolecules. Hence, if a chiral anticancer drug is being prescribed to the patient in the racemic form, it means two or more drugs are being prescribed. Therefore, the chiral separation and analysis of chiral anticancer drugs are important for improving the quality of chiral drug medication. Many metal complexes are used as anticancer drugs, but the conditions become more critical if they have chirality or a chiral moiety, because of which they exist in two or more forms. Because of the presence of chirality or chiral moiety, the complex of metals is termed a chiral metallic complex. Of course, the enantioseparation of the chiral metallic complexes must be done before their prescription. Enantioseparation of the chiral metallic complex will not only provide a pharmaceutically active form to the patient but also reduce the side effects caused by the racemic mixture. Hence, the accessible article reviews the chiral metallic complexes having ruthenium, osmium, palladium, gold, silver, and platinum, etc. as central metal atoms. Besides, the future perspectives regarding the chiral metallic anticancer drugs and the role of their enantioseparation are also discussed. Cancer Enantiomers Metallic drugs Metallic complex Enantioseparation Chiral anticancer drugs Cite this: Eur. J. Chem. 2022, 13(4), 483-490 Journal website: www.eurjchem.com 1. Introduction Cancer is a very dangerous disease for which a large number of drugs are available in the market. Many of them are lab synthesized [1,2], while some of them are plant isolated [3- 5]. A class of drugs that has attracted many scientists involves chirality, due to which they exist in more than one enantiomeric form [6]. Chirality is found in those drugs which have at least one chiral center because of which they exist in more than one form. The most interesting point regarding chiral drugs is the different biological activities of different enantiomers of such drugs [7,8]. Hence, it becomes a great challenge for researchers to find the most biologically active enantiomer of a chiral drug. Not only the removal of the side effect causing enantiomers but also the prescription of the biologically active enantiomer of a chiral drug makes the treatment of cancer improved and superior. Hence, the enantiomeric separation of chiral drugs is very important. It was Louis Pasteur, a French chemist and biologist who laid the foundation of chiral chemistry in 1848 by handpicking the separation of a mixture of two isomers of sodium ammonium tartrate [9,10]. Unfortunately, it took about 100 years to come under this new phenomenon of chirality that plays a pro vital role in plant and animal life along with agricultural, pharmaceutical, and other chemical industries. Amino acids, enzymes, proteins, nucleosides, carbohydrates, hormones, and numerous alkaloids are almost chiral. Hence, the human body environment is chiral due to which stereoselective binding of different enantiomers of chiral drugs takes place differently. Approximately 80% of the drugs available on the market are chiral in nature [11-26]. Therefore, enantiomeric forms of a chiral drug show differences in pharmacology, metabolism, pharmacokinetics and toxicology, etc. The type of biological environment is directly related to the mechanism of chiral drugs. Chirality is one of the significant and inevitable topics in the world of research as well as in pharmaceutical companies. One of its pieces of evidence is the 2001 Nobel Prize in chemistry given to three scientists Dr. William S. Knowles, Pr. K. Barry Sharpless from USA and Pr. Ryori Nyori from Japan for their development of asymmetric synthesis using chiral catalysts in the production of a single enantiomer of chiral drugs or chemicals [27]. Chiral separation of compounds with an exten- sive range of new technologies has US Food and Drug Administration (FDA) endorsed for the evaluation of each enantiomer of racemic drugs in vivo. It also encourages the synthesis and development of new chiral drugs of a single enantiomer [28-30]. Today, one-third of total drugs are chiral, including hydroxylated enones [31], the next generation of platinum drugs [32], asymmetrically synthesized 1,2,4-trioxane [33], etc. Worldwide sales of single-enantiomeric formulations from 2001 to 2005 are given in Table 1. ABSTRACT REVIEW ARTICLE KEYWORDS https://dx.doi.org/10.5155/eurjchem.13.4.483-490.2312 https://www.eurjchem.com/ https://dx.doi.org/10.5155/eurjchem.13.4.483-490.2312 mailto:suhailchem.786@gmail.com http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.13.4.483-490.2312&domain=pdf&date_stamp=2022-12-31 484 Mukhtar and Suhail / European Journal of Chemistry 13 (4) (2022) 483-490 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.483-490.2312 Table 1. Worldwide sales of final formulation of single-enantiomer pharmaceutical products. Therapeutic category 2000 Scales (in $ billions) 2004 Scales (in $ billions) 2005 Scales (in $ billions) CAGR (%) * 2000-2005 Cardiovascular 27.650 34.033 36.196 6 Antibiotic and antifungal 25.942 32.305 34.298 6 Cancer therapeutics 12.201 21.358 27.172 17 Hematology 11.989 20.119 22.439 13 Hormone and endocrinology 15.228 20.608 22.355 8 Central nervous system 9.322 17.106 18.551 15 Respiratory 6.506 12.827 14.708 18 Antiviral 5.890 11.654 14.683 20 Gastrointestinal 4.171 11.647 13.476 26 Ophthalmic 2.265 3.063 3.416 9 Dermatological 1.272 1.486 1.561 4 Vaccines 1.427 2.450 3.100 17 Other 7.128 10.400 13.268 13 Total 130.991 199.056 225.223 11 *CAGR is a compound annual growth rate. This information is from Technology Catalysts International. Table 2. Top-selling single-enantiomer drugs worldwide in the year 2005 scales *. Company Brand name Active pharmaceutical ingredient 2005 Scales (in $ billions) Pfizer, Astellas Lipitor Atorvastatin 12.986 Sanoti-Aventis, Bristol-Myers Squibb Plavix Clopidogrel 6.345 Amgen, Johnson & Johnson Epogen, Procrit Epoetin alfa 5.799 Glaxo Smith Kline Advair, Seretide Fluticasone & Salmeterol 5.465 Genentech, Roche Rituxan, Mab Thera Rituximab 5.166 AstraZeneca Nexium Esomeprazole 4.633 Merck & Co. Zocor Simvastatin 4. 382 Daiichi Sankyo, Bristol-Myers Squibb Mevalotin or Pravachol Pravastatin 3.844 Novartis Diovan Valsartan 3.676 Amgen, Wyeth Enbrel Etanercept 3.567 Johnson & Johnson, Schering-Plough Remicade Infliximab 3.477 Amgen Aranesp Darbepoetin alfa 3.276 Pfizer Zoloft Sertraline 3.256 Merck & Co. Singulair Montelukast 2.976 Sanofi-Aventis Lovenox Enoxaparin 2.668 Genentech, Roche Herceptin Trastuzumab 2.469 Amgen Neulasta Pegfilgrastim 2.288 Lundbeck, Forest Laboratories Cipralex or Lexapro Escitalopram 2.043 Pfizer Zithromax Azithromycin 2.025 Sanofi-Aventis Taxotere Docetaxol 2.003 Sanofi-Aventis Eloxatin Oxaliplatin 1.947 * Sources from Technology Catalysis International and Company Information. Additionally, the single enantiomeric forms sold globally in the year 2005 scales and the names of the companies that produced and marketed these drugs are given in Table 2. Because of the above observation, the pharmacokinetic outlines of enantiomeric drugs administered as a racemate might diverge [34]. In the presented article, our main focus is the chirality of chiral metallic anticancer drugs and their relationship with a cancer diagnosis. 2. Chiral-based metal complexes as anticancer agents Of course, during the drug deposition process, stereoselec- tivity is observed if the drug is taken in the racemic form. This is because different enantiomers of chiral drugs behave differently with chiral targets/environments such as plasma proteins [26]. Therefore, enantioselective drug deposition occurs in the case of chiral drugs. The reason behind the different enantioselective depositions is the different arran- gements of atoms in chiral drugs. Thereafter, chirality becomes a remarkable tool for modern drug discovery and development. Metal-based compounds are also isomeric as their structures have the same molecular composition with different spatial arrangements [35]. The chirality of metal complexes was restricted/limited to its application in asymmetric catalysis, and chiral chemical transformation was notably a powerful approach [36]. According to Dwyer et al. [37], the metal complexes with chirality had an intrinsic relationship with their biological activities. A large number of scientists are associated with the development of metal-based chiral complexes and their anticancer portfolio [38]. Many metals such as platinum, ruthenium, osmium, gold, iridium, rhodium, etc. have been investigated in the context [39]. Their oxidation states, the stable number of ligands, and the coordination number are being studied for the chiral metallic complexes to make them perfectly chiral and more importantly stable [35-39]. Some of the metal complexes of ruthenium, osmium, palladium, gold, silver and platinum, are discussed below. These metals in complex compounds have been used as a central metal atom which are discussed briefly as follows: 2.1. Chiral complex of platinum One of the leading examples of Pt-based chiral anticancer drugs is oxaliplatin {Pt(II)} [40]. Oxaliplatin has two chiral centers, hence, it exists in four enantiomeric forms. The most biologically active form among the four enantiomers is ((R,R)- cyclohexane-1,2-diamine), while other forms are not active. [40]. In 1970, when cis-platin was being tested in initial human trials, a lot of platinum complexes were synthesized side by side to study the relationship between chemical structure and anticancer activity in murine systems [40]. A great breakthrough came when carboplatin and oxaliplatin were approved by FDA [41] (Figure 1) in the years 1989 and 2002, respectively. Carboplatin has the same result as that of cis- platin, but the activity of oxaliplatin showed a wide variety in contrast to the former two platinum species [41]. Oxaliplatin was found effective against colorectal cancer and resistant to malignancy of cancer [41]. Also, it was not effective against squamous cell carcinomas [41]. Regionally different species of the platinum complex were used, such as lobaplatin in China, heptaplatin in Korea, and nedaplatin in Japan [42,43]. Mukhtar and Suhail / European Journal of Chemistry 13 (4) (2022) 483-490 485 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.483-490.2312 Figure 1. Platinum-based chiral anticancer drugs. Many strategies were tested for (i) reduction of their toxicity [43], (ii) improvement in tumor targeting [44], (iii) improvement in biological targeting [45], and (iv) modification of the properties of DNA interaction [46]. The synthesis of some new platinum (II) complexes based on (Δ)- and (Λ)-1,2–bis- (1H-benzimidazol-2-yl)-1,2-ethanediol (Δ-H2bie and Λ-H2bie) enantiomers was reported [47]. Subsequently, the anticancer activities of all synthesized complexes were tested against human breast cancer cell lines (MDA-MB231) and ovarian cancer (OVCAR-8) [47]. It was found that the Δ-H2bie complexes were showing the highest anticancer activity in the taken cell lines [47]. Oxaliplatin got publicity within all platinum species due to its intrinsic stereochemistry [41]. Due to the presence of 1,2-diaminocyclo-hexane (1,2-DACH), Pt (II) complexes also exist in more than one enantiomeric form i.e.; [PtCl2(R,R-,S,S-, and R,S-DACH)]. It is because 1,2-diaminocyclo-hexane has two chiral centers. The variation in anticancer activity, as well as the cytotoxicity of four enantiomeric forms, was directly related with their stereochemical structures. The study of variation in different aspects was done by the national cancer institute (NCI)-60 cancer cell line panel [47]. NCI possesses the data of 60 human cancer lines (https://dtp. cancer.gov/discovery_ development/nci-60/). This data gives us the diverse potential growth inhibitors (GI) of these three isomers. The GI50 value calculation shows [PtCl2(R,R-DACH)] (1.37 μM), [PtCl2(S,S- DACH)] (6.38 μM) and [PtCl2(R,S-DACH)] (11.6 μM) [47]. Among these, only [PtCl2(R,R-DACH)] is under clinical trials. As we know that proteins are chiral structures, enantiomers of chiral drugs show different anticancer activities [47]. 2.2. Chiral complex of gold Stereoselective carbenes are being developed and designed with the starting material, chiral N-heterocyclic ligands, for their application in organic synthesis [48]. Recently, many pharmaceutical applications of N-heterocyclic carbene (NHC) Au(I) complexes have been observed, including antitumor therapy [49]. Mullick et al. studied the in vitro anticancer activity of the chiral NHC dinuclear Au(I) isomer with the chiral ligand (Figure 2) [50]. The cytotoxicity of the racemic complex was confirmed against human tumor cell lines such as HeLa cervical carcinoma and NCI-H23 lung adenocarcinoma) [50]. Besides, the different enantiomeric anticancer activity of the synthesized chiral metallic complex was done on healthy cells such as human embryonic kidney cells (HEK 293) and bronchial epithelial cells (HBE 135-E6E7). [50]. The racemic mixture showed discreetly cytotoxicity against cell lines, side by side two pure enantiomers (S,S,S,S)- and (R,R,R,R)-posed questions and further investigation was required. In addition, Li et al. [51] studied the P-stereogenic phosphine ligand-based enantio- meric complex. The pure Au(I) enantiomers were observed (Figure 2) and it was seen that both showed good antitumor activity against adherent and suspension cancer cells [51]. The most important and notable fact regarding the synthesized drug was the least toxicity for healthy lymphocytes. They also studied pure chiral diphosphine-digold(I) complexes [51]. Interestingly, the (R,R)-cytotoxicity was found to be similar to that of the (S,S)-enantiomer [51]. The (R,R)-enantiomer was found to show more toxicity (30.1%) against healthy mammary gland cells than the (S,S)-enantiomer (3.1%) under similar conditions [51]. It was just because of the stereochemistry in the NHC gold complexes that affects its biological properties [51]. 2.3. Chiral complex of ruthenium Organometallic ruthenium is a bright star in the context of chemotherapy. Several organometallic compounds of ruthe- nium have been synthesized and published [52-54]. Unfortu- nately, a fever number of chiral Ru complexes have been reported [55]. Meggers Atilla-Gokcumen et al. [56] and Smalley [57] reported the bidentate staurosporine ligand-based chiral Ru complex as a protein kinase inhibitor. Two purified staurosporine-type enantiomers, DW1 and DW2 (Figure 3) were separated and the anticancer activity of each enantiomer was checked [56]. 486 Mukhtar and Suhail / European Journal of Chemistry 13 (4) (2022) 483-490 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.483-490.2312 Figure 2. Gold-based chiral anticancer drugs. Figure 3. Ruthenium-based chiral anticancer drugs. During the in vitro assay, it was found that DWI showed IC50 2 and 2.5 nM for GSK-3α and GSK-3β (protein kinase inhibitors), respectively [57]. Similarly, DW2 showed IC50 9 and 15 nM for the same protein kinase inhibitors at 100 μM ATP [56]. The R- complex (3) (Figure 3) showed not only an inhibitory effect against GSK-3β with IC50 = 0.35 nM but also anticancer activity at a concentration of 100 μM ATP. It was 257 times higher compared to the S-enantiomer (4) (Figure 3) with IC50 = 90 nM at 100 μM ATP [56]. Additionally, the 1205Lu melanoma cells were used to test anticancer activity for 72 h. After this study, DW1 was found to be more potent than DW2 against protein kinase inhibitors [57]. A series of new chiral Ru(II) polypyridyl complexes (1-5) with the general formula {Δ/Λ-[Ru(bpy)2(X,Y- sal)]BF4} (bpy = 2,2′-Bipyridyl; X,Y-sal = 5-bromosalicyl aldehyde (1), 3,5-dibromosalicylaldehyde (2), 5-chlorosalicyl aldehyde (3), 3,5-dichlorosalicylaldehyde (4) and 3-bromo-5- chlorosalicylaldehy (5) were also synthesized [58]. Subse- quently, the anticancer activities of all synthesized complexes were tested against human lung cell lines (A549). Among all synthesized compounds, only three complex compounds (1, 2 and 5) were found as active drugs because they were showing the highest anticancer activity against the taken cell lines [58]. 2.4. Chiral complex of osmium Although scanty data was found about the osmium metallic complexes, they have shown anticancer activity, hence, they have been considered as potential anti-cancer drugs. [59,60]. Mukhtar and Suhail / European Journal of Chemistry 13 (4) (2022) 483-490 487 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.483-490.2312 Figure 4. Osmium-based chiral anticancer drugs. Sadler et al. [60] reported chiral Os(II) arene iminopyridine complexes, the derivative of two unsymmetric R- and S-ImpyMe ligands, (R/S-ImpyMe = N-(2-pyridylmethylene)-R/S-1-phenyl- ethylamine). The bidentate chelating chiral ligand is utilized for the pure diastereomeric separation with configuration (ROs, RC)- or (SOs, SC)-osmium complexes by fractional crystal- lization (Figure 4) [60]. The osmium iodide complex (Figure 4) treatment on A2780 human ovarian tumor cells depicted its strong potential cytotoxicity as compared to the osmium chloride complex (Figure 4) which showed moderate antitumor activity [60]. The anticancer activity of the R-enantiomeric form of Os complex was found higher as compared to its S- enantiomeric form. The correct reason for it, is not known yet. 2.5. Chiral complex of silver Silver complexes based on chirality have also shown good results in cancer treatment [61]. A research group prepared chiral silver(I) diaminocarbene complexes using imidazolium salt [62] because imidazolium and its derivatives have shown tremendous anticancer activity [1]. Besides, another research group synthesized N-heterocyclic carbene ligands (NHC) and their Ag(I) complexes [51]. The anticancer activity of the synthesized complexes was checked against MCF-7, MDA-MB- 231 and DU-145 cancer cells [51]. After that, it was found that the Ag(I) single bond NHC complexes showed a dose and time- dependent cytotoxic activity against all cell lines. The synthesis of some new silver(I) complexes based on (Δ)- and (Λ)-1,2–bis- (1H-benzimidazol-2-yl)-1,2-ethanediol (Δ-H2bie and Λ-H2bie) enantiomers was reported [47]. Subsequently, the anticancer activities of all synthesized complexes were tested against human breast cancer cell lines (MDA-MB231) and ovarian cancer (OVCAR-8) [47]. It was found that the Δ-H2bie complexes were showing the highest anticancer activity in the taken cell lines [47]. 2.6 Chiral complex of palladium The importance of Pd-complexes based on chirality can not be denied because they have a unique position in chiral complexes of transition elements [63]. Synthesis of some new palladium (II) complexes based on (Δ)- and (Λ)-1,2–bis-(1H- benzimidazol-2-yl)-1,2-ethanediol (Δ-H2bie and Λ-H2bie) enantiomers was reported [47]. Subsequently, the anticancer activities of all synthesized complexes were tested against human breast cancer (MDA-MB231) and ovarian cancer (OVCAR-8) cell lines. It was found that the Δ-H2bie complexes were showing the highest anticancer activity in the taken cell lines [47]. Some researchers investigated the influence of chirality and halogen atoms on the anticancer activity of enantiopure palladium(ii) complexes (J1-J8) derived from chiral amino-alcohol Schiff bases and 2-picolylamine [47]. It was found that the J2 and J4 complexes showed the highest anticancer activity. 3. The chiral drug development process One of the striking features in the introduction of chirality in a drug moiety is the increasing complexity of specific targets, which means greater diversity of compounds must be disclosed [64]. Chiral drugs have two principal circumstances for the pharmaceutical industry: first, the conversion of racemic drugs into either of the two enantiomers [65,66] and second, the fresh (de novo) development of a pharmaceutically pure enantiomer, typically called a eutomer [67]. By developing a novel moiety for not only direct entry but also drug approval and intro- duction in the market, we prefer an unambiguous design. New terminology has been introduced such as NCE (new chemical entity), NBE (new biological entity), NME (new molecular entity) and NAS (new active substance) by medicinal researchers and scientists for drug discovery and development with some uncertainty. A new term, NTE (new therapeutic entity) was also suggested by Branch et al. [68] for a new drug design. From 1994 to 2011 (as the first scenario), the chiral switching process has been a vital component in drug develop- ment portfolios. From 2001 to 2011, one-third of the chiral switch was approved such as levocetirizine, dexlansoprazole and esomeprazole. However, there is no legal authority under the FDA to test the efficiency of a single enantiomer as compared to the previously developed racemate [69]. 488 Mukhtar and Suhail / European Journal of Chemistry 13 (4) (2022) 483-490 2022 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.13.4.483-490.2312 In the case of de novo development of a pure enantiomeric drug, three ways are followed by a pharmaceutical company to access chiral products: (1) Use of natural products (chiral pool) as a starting material for pure enantiomer synthesis, (2) emp- loyment of stereoselective synthesis that includes enzymatic and biological procedures and (3) chiral resolution (a non- stereoselective synthetic protocol) for racemic separation. In all steps mentioned above, the pharmaceutical company should have comprehensive specification data for the final product to guarantee strength, identity, purity, and quality in context with stereochemistry [70]. For initial testing, the amount of enormous molecules in milligrams is required during the disco- very stage. As per FDA protocol [70], both enantiomers are to be biologically tested for the new therapeutic entity, so that the development of chiral active drugs racemate can be more appropriate than stereoselective syntheses. It is not worth the time and is cost-efficient. Non-stereoselective synthesis of a single enantiomer on a large scale reduces time and cost. For the separation of enantiomeric forms, many methods are followed such as crystallization, diastereomeric salt or complex formation, and chiral chromatography [71]. This formulation has become a better protocol for drug discovery in the pharmaceutical industry and has been shown to be an accelerator in drug development [71,72]. A lot of transfor- mations occurred significantly for the potential API (Active Pharmaceutical Ingredient) processer in the year 2015 [73] 4. Toxicology It cannot be denied that different enantiomers of a chiral drug frequently have large differences in pharmacodynamics and pharmacokinetics. It may lead us to stereoselective toxicity. One of the enantiomeric forms of a chiral drug is the form of interest, whereas the other form is not. This decides the toxicity of that enantiomer which is not of interest [74]. The best example is Dopa (dihydroxy-3,4 phenylalanine) which acts as a dopamine precursor for Parkinson’s disease treatment [75]. The Dopa availability in the market is in the racemic form (D,L), the D-isomer has severe toxicity causing agranulocytosis, whereas L-Dopa i.e; levorotatory acts as the therapeutic agent. One more example is tetramisole (nematocide) firstly used in racemic form. It causes many side effects such as headache, vomiting, vertigo, and abdominal pain, due to its d-isomer. In contrast, its l-isomer, namely levamisole, is used in medicine [75]. There are so many chiral drugs in the market that exhibit toxic effects [76], and are still to be enantioseparated. Many chiral anticancer drugs are cytotoxic due to their chemical reactivity [76]. It is not a surprise that many anticancer drugs have toxicities toward healthy cells [76]. Therefore, an approach to reduce stereo-selective toxicity must be exploited. One of the examples is cyclophosphamide with a chiral center at the phosphorous atom, due to which it exists in more than one enantiomeric form [76]. According to Cox et al. [77], the (D)-enantiomer showed two times greater therapeutic index (LD50/ID90) as compared to the (1)-enantiomer against the ADJ/PC6 cell turnover in mice. However, there was no significant therapeutic advantage gained using a single enantiomer. 5. Pharmacokinetics and metabolism The proper procedures of absorption, distribution, elimi- nation, and metabolism are the vital variable of drug action at the receptor site in vivo. The discernment potential between two enantiomers at every stage of proper procedure provides us the relevant information about stereospecific and stereo- pharmacokinetics drug assays [78]. The pharmacokinetics and metabolic profile differences in two enantiomers of chiral anticancer drugs can be demonstrated qualitatively as well as quantitatively [79-85]. According to Mehvar et al. [83], many racemic drugs are available such as tocainide, mexiletine, flecainide, propafenone, encainide, disopyramide etc. The first step of ADMET for these chiral drugs appears to be non-stereo- selective. However, the other variables such as distribution, metabolism, and renal excretion respond to one enantiomer as compared to others. In distribution, blood plasma protein binding is stereoselective for most of the chiral drugs mentioned above leading to double-fold variances between two enantiomers [82,86]. 6. Conclusions In the pharmaceutical industry, the enormous availability of only a single enantiomer in the market makes it not only strong but also better tolerable for cancer treatment. Hence, before launching a chiral drug into the market, the enantiomeric forms must be separated by a pharmaceutical company. There are many cases noted where only one enantiomer has more therapeutics than the other enantiomers. Hence, the separation of enantiomeric forms of a chiral compound must be done first, so that a single biologically active form can be provided to the patient. Noticeably, it will reduce the toxicity caused by a racemic mixture. Of course, the metal-based complexes are also an active part of the chiral family because of the chiral moiety. It is a growing field of research in the discovery of anticancer drugs. The metals used are ruthenium, osmium, palladium, gold, silver, and especially platinum, which are highly active in many anticancer drugs. 7. Future perspectives Of course, the body of all living things is suitable only for one of the more enantiomeric forms of chiral drugs. New nano- formulations of chiral anticancer drugs are required for future perspectives. In addition, new methods of enantiomeric separa- tion are to be developed for special racemic anticancer drugs. Spirocyclic oxindoles are another promising drug that is a potent inhibitor of the p53-MDM2 interaction. Different hetero- cyclic substituents attached to the core of oxindoles led us to discover and develop new chiral anticancer drugs. Overall, in the pharmaceutical market, single enantiomeric drugs will grow, and their higher growth will mature the medicinal market in the case of cancer treatment in the modern era. Disclosure statement Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: All ethical guidelines have been adhered. CRediT authorship contribution statement Conceptualization: Mohammad Suhail; Writing - Review and Editing: Mohammad Suhail; Literature survey: Sofi Danish Mukhtar. ORCID and Email Sofi Danish Mukhtar danishsofi7@gmail.com https://orcid.org/0000-0002-1543-5942 Mohammad Suhail suhailchem.786@gmail.com mohd.suhail159068@st.jmi.ac.in https://orcid.org/0000-0002-1641-4633 References [1]. Ali, I.; Lone, M. N.; Aboul-Enein, H. Y. Imidazoles as potential anticancer agents. Med. Chem.Comm. 2017, 8, 1742–1773. [2]. Ali, I.; Nadeem Lone, M.; Suhail, M.; Danish Mukhtar, S.; Asnin, L. Advances in nanocarriers for anticancer drugs delivery. Curr. Med. 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Life Sci. 2021, 1166, 122550. [86]. Ali, I.; Suhail, M.; Alothman, Z. A.; Abdulrahman, A.; Aboul-Enein, H. Y. Drug analyses in human plasma by chromatography. In Handbook of Analytical Separations; Elsevier, 2020; pp. 15–46. Copyright © 2022 by Authors. This work is published and licensed by Atlanta Publishing House LLC, Atlanta, GA, USA. The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Chiral-based metal complexes as anticancer agents 2.1. Chiral complex of platinum 2.2. Chiral complex of gold 2.3. Chiral complex of ruthenium 2.4. Chiral complex of osmium 2.5. Chiral complex of silver 2.6 Chiral complex of palladium 3. The chiral drug development process 4. Toxicology 5. Pharmacokinetics and metabolism 6. Conclusions 7. Future perspectives Disclosure statement CRediT authorship contribution statement ORCID and Email References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField17: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: PrintField27: