{"id":60880,"date":"2024-09-30T12:00:55","date_gmt":"2024-09-30T12:00:55","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=60880"},"modified":"2024-10-11T16:12:58","modified_gmt":"2024-10-11T16:12:58","slug":"structural-variance-of-doxorubicin-and-anthracycline-analogues-as-topoisomerase-alpha-and-beta-top2a-and-top2b-inhibitors-potential-design-of-analogue-candidates-of-less-side-effects-on-cardiomyocy","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no3\/structural-variance-of-doxorubicin-and-anthracycline-analogues-as-topoisomerase-alpha-and-beta-top2a-and-top2b-inhibitors-potential-design-of-analogue-candidates-of-less-side-effects-on-cardiomyocy\/","title":{"rendered":"Structural Variance of Doxorubicin and Anthracycline Analogues as Topoisomerase Alpha and Beta (Top2a and Top2b) Inhibitors and Potential Design of Analogue Candidates of Less Side Effects on Cardiomyocytes"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Scaffolds especially those derived\nfrom natural sources are of vital biological importance as antineoplastic\nagents. Anthracyclines dates back to 1960\u2019s and their primary isolation\nrevolutionized the treatment modalities for many cancers, namely solid tumors\nand neoplastic types.  Early agents known\nwere doxorubicin and daunorubicin, categorized as antibiotics having high\naffinity for Gram-positive bacteria but exhibited significant cytotoxicity\nwhich led to their exploitation as anticancer drugs.1-4<\/sup><\/p>\n\n\n\n

Anthracyclines are currently used\nin combination for treatment of breast cancer with the standard CMF (cyclophosphamide, methotrexate, and fluorouracil)\nregimen5<\/sup>, as well as other combination.6,7<\/sup> The enclosure\nof an anthracycline has been proved to decrease mortality rates in women.\nAnthracyclines are also used for different clinical indications.8,9<\/sup> <\/p>\n\n\n\n

Several anthracyclines obtained\nvia biosynthesis or chemical modifications. An alarming aspect of their\nclinical use is the toxic risks associated with their accumulation. The aim has\nalways been the development of safer anthracyclines, with broader spectrum of\nactivity against different tumors, as well as enhanced selectivity. Most of the\nfirst, second and third generations share an amino-sugar moiety essential for\nDNA binding and intercalation.10-12<\/sup> The main drawback associated\nwith the use of anthracyclines lies in their considerable affinity to the\ncardiac tissue, lead to cardiotoxicity.13<\/sup>  In order to avoid\nand\/or minimize the risk of cardiomyopathy and congestive heart failure, this\nwork relates the extent of cardiotoxicity and structural differences in each\ndrug by considering the topology of the fully optimized 3D-structure. The\nphysicochemical data of the optimized structures are also considered. Anthracyclines\nbind to topoisomerases II and DNA resultant in a ternary\ncomplex, and preventing re-ligation.14,15<\/sup> The cardiotoxicity involves production\nof free-radical, which results in damaging DNA, proteins, and lipids and leads\nto cellular dysfunction.16<\/sup> Thorough, investigation of occurrence in\ncells and organs of topoisomerases mentioned\nthat doxorubicin targets both of topoisomerases namely, alpha (Top2A) and beta\n(Top2B). Human topoisomerase TOP2A is encoded by the Top2A<\/em>–<\/em>gene on chromosome-17q21-22, and Top2B is\nencoded by the Top2B<\/em>-gene on chromosome-3p24. Cardio-myocytes express Top2B but not TopP2A.15-18<\/sup><\/p>\n\n\n\n

In area of drug discovery scientists usually locking in the main pharmacophore that fits the pharmaco-dynamic interactions. Derivatization on the skeleton rely on addition, removal, and\/or modification of adaptable entities on the skeleton that lead to selectivity and specificity whenever isoforms found. Considering cardiomyocytes that express Top2B but not Top2A and the inhibitor\u2019s level of effects and side effects.19-22<\/sup> Topoisomerase-2 necessitates ATP to act. It makes a temporary break and rejoin via trans-esterification utilizing phosphate-diester (Figure 1). Thus, inhibition of topoisomerase II preventing DNA repair and causing DNA damage and cell-death. 23<\/sup> <\/p>\n\n\n\n

Several strategies are mentioned for tumor selectivity such as (a) – It can be boosted if aided by specific transporters to malignant tissues in specific organs,24-27<\/sup> (b) – Liposomal formulations as well as binding to polymers (31), and (c) – Prodrug preparations that are favorably activated intracellular.28-33<\/sup> These tactics were used to increase selectivity and reduce undesirable effects.34,35<\/sup> This work is a thorough structural and topological investigation of anthracyclines. Molecular modeling of each selected approved drug or candidate structure studied as fully optimized at full self-consistent field (SCF) levels by using MOPAC36,37<\/sup>; a general molecular orbital package implemented with molecular mechanics software MMXPC.38<\/sup> This study is to find the structural modalities differentiating between toxic anthracyclines, safer anthracyclines, anthracyclines bearing both antibacterial and anticancer effects, and the related tetracyclines. It is a continuation of our interest in compounds bearing anti-cancer, anti- inflammatory and antimicrobial activities.24,39-52<\/sup> The answer for topology differences between approved antimicrobial and antineoplastic tetracyclic structures can be gathered in throughout the article.<\/p>\n\n\n\n\n\n
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Table 1: <\/strong>Non anthracycline topoisomerase-2 inhibitors.<\/strong><\/p>\n

\u00a0<\/p>\n

Click here to view Table<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

\u00a0<\/p>\n\n\n\n
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Figure 1: <\/strong>Topoisomerase-II mechanism of releasing the supercoiling and rejoining DNA.<\/strong><\/p>\n

\u00a0<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Structural Characteristics of Drugs Approved Candidates of Anthracyclines  <\/strong><\/p>\n\n\n\n

The structural\ndifferences of derivatives in medical use mainly attributed to three substructures\nin the tetracyclic skeleton namely C-4 (Ring A), C-7 and C-9 (Ring D). The\nentities involved are amino-sugar (Figure 2, R1<\/sup>), the minor\ndifferences of aglycone moiety (Figure 2, R2<\/sup>) and the whole acyl\ngroup (Figure 2, R) at C-9.53-76<\/sup> The important\nphysicochemical data for these drugs and\/or candidates are considered as\ncalculated partition coefficient.54,55-76<\/sup><\/p>\n\n\n\n

The calculated partition coefficients of clinically used analogs range from CLogP: 1.734 for the more lipid soluble, like idarubicin to CLogP: 0.648 for the less lipid soluble one like doxorubicin. Lipid solubility is important for effects and side effects as well.56-76<\/sup> <\/p>\n\n\n\n\n\n
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Figure 2: <\/strong>Clinically useful anthracyclines, the orphan drug amrubicin<\/strong> and annamycin<\/strong>.<\/strong><\/p>\n

<\/p>\n

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Brief Biosynthesis of Anthracyclines<\/strong><\/p>\n\n\n\n

Biosynthesis of doxorubicin involves many steps reported in conventional articles. It starts by a three carbons unit; propanoyl-CoA; (Figure 3) which combines by a decarboxylation coupling with malonyl-CoA. Malonyl-Co-A is, repeatedly added via carriers after losing carbon dioxide in each step to provide a skeleton of 21 carboxylic acid bearing 10 carbonyl groups.2,79-81<\/sup> The poly-carbonyl 21-carbon acid manipulated successively by different enzymes to yield tricyclic; alkanoic acid, then to the aglycone; rhodomycinone.  Rhodomycinone undergoes structural modifications and coupling with amino-sugar, via<\/em> several bio-transformations to provide doxorubicin.82,83<\/sup><\/p>\n\n\n\n\n\n
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Figure 3: <\/strong>Biosynthesis of doxorubicin.<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Medical Importance of Anthracyclines in Cancer Treatment<\/strong><\/p>\n\n\n\n

Anthracyclines are still very important for treatment of acute\nlymphocytic and chronic myelogenous leukemia; the disease in which the bone\nmarrow makes too many white blood cells. Doxorubicin also, succeeded to show a\nsubstantial efficacy against solid tumors.84<\/sup> Several types of solid\ntumors are responsive to doxorubicin, as breast carcinoma, small-cell lung\ncarcinoma, and ovarian carcinoma.85<\/sup> <\/p>\n\n\n\n

Pharmacological Effects and Toxicological Profiles of Anthracyclines<\/strong><\/p>\n\n\n\n

Not only disrupting topoisomerase-II-mediate DNA\nrepair, anthracyclines also, produce free radicals by reversible quinonoid\ntransformation. Free radicals damaging membrane, DNA and proteins.  In addition, reactive oxygen can make\nepoxidation of fatty acids leading to membrane and DNA damage, oxidative\nstress, and triggering apoptosis.86,87<\/sup> Alternatively, doxorubicin\ncan enter the nucleus and poison topoisomerase-II, also resulting in DNA damage,\ncell cycle control and cell death.88-91<\/sup> <\/p>\n\n\n\n

The cumulative dose-dependent cardiac toxicity of\ndoxorubicin represents unwanted health problem from essential medicines. There are\nsome differences between the anthracycline\u2019s congeners in toxicological\nprofile and upon comparing their ability to induce topoisomerase II-mediated\nDNA cleavage.92-94<\/sup> Cardiac toxicity as reported in several articles\nattributed to the cellular oxidative stress induced by free radicals.\nUnfortunately, doxorubicin preferentially interacts with cardiomyocytes, and\nthe side effects resulted as reflection of free radicals on DNA, protein and\nlipid as reported elsewhere (Figure 4).95-97<\/sup> <\/p>\n\n\n\n

Oxidative stress resulted as reflection of coordination reactions between metals such as iron and functionalities of the co-planar system at rings B and C (Figure 4). The complex of metal and anthracyclines catch soluble oxygen that accordingly producing superoxide. Superoxide dismutase: the natural cellular antioxidant change catalyzes the disproportionation of superoxide to be converted into two less damaging species.  <\/p>\n\n\n\n\n\n
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Figure 4: <\/strong>Anthracyclines mediated free radical formation and biological effects.<\/strong><\/p>\n

<\/p>\n

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Comparative Cardiac Toxicity and Potential Chemical Modifications to Decrease Side Effects<\/strong><\/p>\n\n\n\n

The relevant chemical entities involved in oxidative stress-are mentioned on tetracyclic structure of anticancer as well as antibacterial activities. The group of drugs and candidates realized for elaboration of topology and SAR study (Figure 5). The structural entities responsible for chelation and free radical production are highlighted. Compounds are mentioned by numbers and names (Figure 2 and Table 2).  An anthracycline; Compound 14; Mutamycin E (Figure 5) fulfills the features of doxorubicin except the C-9 alpha-hydroxy acetyl group. This compound as active but not considered for further preclinical effects as anticancer. On the other-hand, tetracycline (Figure 5, Compound 15) which has no amino-sugar attachment at C-7 is in use as antibacterial medicine with high safety. The two compounds 14 and 15 are included with anthracyclines to elaborate the important topological differences on biological activity. The differences are important to verify the clinical usefulness of tetracyclic structures as anticancer and\/or antibacterial activity.  <\/p>\n\n\n\n\n\n
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Figure 5: <\/strong>Selected tetracyclic structures of different biological activities.<\/strong><\/p>\n

\u00a0<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

\u00a0<\/p>\n

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Table 2: <\/strong>Important investigational and experimental anthracyclines.<\/strong><\/p>\n

\u00a0<\/p>\n

Click here to view Table<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Doxorubicin (Compound 1, Figure 2) is in wide use especially in solid tumors and used admixed with other agents to reduce as possible the side effects on heart (98).  In addition to the entities that are highlighted for their contribution in free radical formation (Figure 4), doxorubicin has three main groups represent the differences with congeners. The most important entities are: <\/p>\n\n\n\n

A coplanar C-4-methoxy group. <\/p>\n\n\n\n

Amino-sugar (pyran ring) substituent attached to C-7 of three groups a methyl, a hydroxyl and one amino group.<\/p>\n\n\n\n

A hydroxy acetyl group-oriented beta<\/em> as a substituent at C-9. <\/p>\n\n\n\n

Daunorubicin has the same structural entities at\nC-4 and C-7 but having acetyl instead of hydroxyl-acetyl at C-9. This small\ndifference led to a product of less side effect on heart.98-100<\/sup> <\/p>\n\n\n\n

The (Figure 6) shows a graphical representation of doxorubicin G1 as coplanar four fused rings part C, the substituent at C-7 as part A and the substituent at C-9 as part B. Doxorubicin G2 as optimized at full self-consistent field (SCF) levels by using MOPAC; a general molecular orbital package implemented with molecular mechanics software MMXPC.36-38<\/sup> In the general substituted tetracyclic system, the structure part C is planar. Part B (the C-9 substituent) appears perpendicular up with the planar C and the amino-sugar; part A appears perpendicular down to the planar system. The following monographs are introduced for comparative purposes between tetracyclic structures of anticancer activity concomitant with severe side effect on heart with those having less side effect and with the others bearing antimicrobial activity rather than cytotoxicity.  <\/p>\n\n\n\n

Table 3: Important used drugs, investigational, and experimental tetracyclic structures optimized at full self-consistent field (SCF) levels by using MOPAC.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Compound<\/strong><\/p>\n<\/td>\n

\n

% PSA<\/strong><\/p>\n<\/td>\n

\n

% UnSA<\/strong><\/p>\n<\/td>\n

\n

SE<\/strong><\/p>\n<\/td>\n

\n

Str<\/strong><\/p>\n<\/td>\n

\n

bnd<\/strong><\/p>\n<\/td>\n

\n

DM<\/strong><\/p>\n<\/td>\n

\n

HF<\/strong><\/p>\n<\/td>\n

\n

CLogP<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Compound 1: Doxorubicin<\/p>\n<\/td>\n

\n

37.72<\/p>\n<\/td>\n

\n

14.25<\/p>\n<\/td>\n

\n

-97.6<\/p>\n<\/td>\n

\n

1.480<\/p>\n<\/td>\n

\n

9.203<\/p>\n<\/td>\n

\n

7.433<\/p>\n<\/td>\n

\n

-383,43<\/p>\n<\/td>\n

\n

0.648<\/p>\n<\/td>\n<\/tr>\n

\n

Compound 2: Daunorubicin<\/p>\n<\/td>\n

\n

35.26<\/p>\n<\/td>\n

\n

14.25<\/p>\n<\/td>\n

\n

-99.2<\/p>\n<\/td>\n

\n

1.422<\/p>\n<\/td>\n

\n

8.306<\/p>\n<\/td>\n

\n

5.598<\/p>\n<\/td>\n

\n

-346.62<\/p>\n<\/td>\n

\n

0.959<\/p>\n<\/td>\n<\/tr>\n

\n

Compound 3: Epirubicin<\/p>\n<\/td>\n

\n

37.84<\/p>\n<\/td>\n

\n

14.35<\/p>\n<\/td>\n

\n

-98.5<\/p>\n<\/td>\n

\n

1.509<\/p>\n<\/td>\n

\n

8.875<\/p>\n<\/td>\n

\n

7.52<\/p>\n<\/td>\n

\n

-384.24<\/p>\n<\/td>\n

\n

0.648<\/p>\n<\/td>\n<\/tr>\n

\n

Compound 4: Idarubicin<\/p>\n<\/td>\n

\n

35.72<\/p>\n<\/td>\n

\n

16.02<\/p>\n<\/td>\n

\n

-84.4<\/p>\n<\/td>\n

\n

1.373<\/p>\n<\/td>\n

\n

7.091<\/p>\n<\/td>\n

\n

6.595<\/p>\n<\/td>\n

\n

-310.49<\/p>\n<\/td>\n

\n

1.734<\/p>\n<\/td>\n<\/tr>\n

\n

Compound 5: Amrubicin<\/p>\n<\/td>\n

\n

45.36<\/p>\n<\/td>\n

\n

26.55<\/p>\n<\/td>\n

\n

-73.4<\/p>\n<\/td>\n

\n

1.688<\/p>\n<\/td>\n

\n

5.960<\/p>\n<\/td>\n

\n

6.245<\/p>\n<\/td>\n

\n

-201.03<\/p>\n<\/td>\n

\n

0.113<\/p>\n<\/td>\n<\/tr>\n

\n

Compound 6:  Annamycin<\/p>\n<\/td>\n

\n

37.76<\/p>\n<\/td>\n

\n

14.04<\/p>\n<\/td>\n

\n

-110.0<\/p>\n<\/td>\n

\n

1.871<\/p>\n<\/td>\n

\n

8.839<\/p>\n<\/td>\n

\n

5.608<\/p>\n<\/td>\n

\n

-369.53<\/p>\n<\/td>\n

\n

1.599<\/p>\n<\/td>\n<\/tr>\n

\n

Compound 10:<\/p>\n

13-deoxy-doxorubicin<\/p>\n<\/td>\n

\n

30.66<\/p>\n<\/td>\n

\n

13.30<\/p>\n<\/td>\n

\n

-103.1<\/p>\n<\/td>\n

\n

1.290<\/p>\n<\/td>\n

\n

7.265<\/p>\n<\/td>\n

\n

2.758<\/p>\n<\/td>\n

\n

-397.34<\/p>\n<\/td>\n

\n

1.444<\/p>\n<\/td>\n<\/tr>\n

\n

Compound 11: Esorubicin<\/p>\n<\/td>\n

\n

34.89<\/p>\n<\/td>\n

\n

13.88<\/p>\n<\/td>\n

\n

-95.6<\/p>\n<\/td>\n

\n

1.394<\/p>\n<\/td>\n

\n

7.440<\/p>\n<\/td>\n

\n

5.655<\/p>\n<\/td>\n

\n

-343.02<\/p>\n<\/td>\n

\n

0.879<\/p>\n<\/td>\n<\/tr>\n

\n

Compound 12: Zorubicin<\/p>\n<\/td>\n

\n

27.45<\/p>\n<\/td>\n

\n

20.97<\/p>\n<\/td>\n

\n

-128.6<\/p>\n<\/td>\n

\n

13.850<\/p>\n<\/td>\n

\n

12.000<\/p>\n<\/td>\n

\n

13.886<\/p>\n<\/td>\n

\n

-303.78<\/p>\n<\/td>\n

\n

3.032<\/p>\n<\/td>\n<\/tr>\n

\n

Compound 14: Mutamycin E<\/p>\n<\/td>\n

\n

32.68<\/p>\n<\/td>\n

\n

14.22<\/p>\n<\/td>\n

\n

-115.0<\/p>\n<\/td>\n

\n

1.930<\/p>\n<\/td>\n

\n

9.837<\/p>\n<\/td>\n

\n

6.179<\/p>\n<\/td>\n

\n

-447.55<\/p>\n<\/td>\n

\n

2.613<\/p>\n<\/td>\n<\/tr>\n

\n

Compound 15: Tetracycline<\/p>\n<\/td>\n

\n

44.55<\/p>\n<\/td>\n

\n

15.61<\/p>\n<\/td>\n

\n

-143.7<\/p>\n<\/td>\n

\n

1.717<\/p>\n<\/td>\n

\n

7.152<\/p>\n<\/td>\n

\n

5.215<\/p>\n<\/td>\n

\n

-238.7<\/p>\n<\/td>\n

\n

0.911<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

PSA = Polar Surface Area, UnSA = Unsaturated Surface Area, SE = Standard Entropy, Str = stretching, Bnd = bending, DM = dipole moment, HF = heat of formation, and ClogP = Calculated partition coefficient for n-octanol\/water obtained from chemdraw 8 ultra.<\/p>\n\n\n

Candidates of analogs as anticancer compounds, in\naddition to compd. 14 a natural product (101) bearing antibacterial and cytotoxic activities and\ntetracycline are studied as 3D-optized structures at full SCF and outlined in (Table\n4).101,102<\/sup> A very important value gathered from the table is the\ntetracycline having very high percentage of polar surface area (% PSA, 44.6%).\nThe candidates failed in clinical development like compound 10 and compound 12\nbearing the least percentage of polar surface area (% PSA 22.5 and 30.6%). It\nalso indicates the importance of the ketonic-function of substituent at C-9.103-106<\/sup>\n<\/p>\n\n\n\n

The methods by which anthracyclines can be prepared are\nsemi synthesis,\ngenetically engineered Streptomyces peucetius<\/em> and from total synthesis.107-110<\/sup><\/p>\n\n\n\n

The\nattempts to reduce the incidence of\ncardiotoxicity can be made if several modifications can be applied. <\/p>\n\n\n\n

First is to remove the methoxy substituent at C-4\nof the skeleton. The drugs and candidate such as compounds 4, 5 and 6 are of\nless cardiotoxic effect. Methoxy group on aromatic systems donates electrons and,\nin these cases, it may increase the chelation power of the keto-enol systems\nundergoing the chelation with iron. Other groups can be tried.111,112<\/sup>\n<\/p>\n\n\n\n

Second is the ketonic group (C=O) of the C-9 substituent\nappear of high importance for tumoricidal action (Topoisomerase II\u03b1) but also\nin the pathogenesis of cardiotoxicity (Topoisomerase II\u03b2). Replacement by (CH2<\/sub>)\ndecreases the effect topoisomerase II\u03b1 but increases the cardiotoxicity;\ntopoisomerase II\u03b2.  Compd. 10 bears less\neffects than doxorubicin as anticancer but high side effects on heart. The\nphysicochemical properties of compound 10 appears of less percentage of polar\nsurface area % PSA and less dipole moment than all the clinically useful\nanthracyclines.113,114<\/sup> <\/p>\n\n\n\n

Third is the sugar at C-7: In doxorubicin there\nare three substituents on pyran ring methyl, hydroxyl, and amino groups of\nspecific stereochemistry. Changing the stereochemistry of a single group in\npyran provided a potent with less cardiotoxic derivative compound 3.  Amino group of pyran at C-7 which has been\nrigorously mentioned as essential for activity, two derivatives (compound 5 and\n6) one of which is orphan drug, compound 5 having no amino group in the C-7\npyran entity. The presence of a powerful hydrogen bond acceptor and donor such\nas NH2<\/sub> or OH groups.115-118<\/sup> <\/p>\n\n\n\n

Fourth is the possible absence of one of the parts\nat C-7 and C-9 mentioned as A and B in the topology graph (Figure 6) decreases\nthe cytotoxicity relative to all of the anthracyclines considered for\ndevelopments like compound 14.   <\/p>\n\n\n\n

Fifth, is the absence of both parts at C-7 and C-9 mentioned as A and B in the topology graph (Figure 6) abolishing the cytotoxic effect and emerging the antibacterial activity. The compound 15, physico-chemical data in Table 3, demonstrates a high percentage polar surface area of compd. 15 (Table 4) than all the derivatives % PSA exceeding 44%. In silico<\/em> calculation of ADME (Table 4) showed many differences between compound 15 and others in partition coefficient, water solubility, bioavailability score, and even in not being a good substrate for oxidase enzymes. <\/p>\n\n\n\n

Table 4: Important used drugs, investigational, and experimental tetracyclic structures calculated in-silico- for pharmacokinetics by Swiss ADME.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

No.<\/strong><\/p>\n<\/td>\n

\n

Compound<\/strong><\/p>\n<\/td>\n

\n

MR<\/strong><\/p>\n<\/td>\n

\n

Consensus Log P<\/strong><\/p>\n<\/td>\n

\n

Pgp substrate<\/strong><\/p>\n<\/td>\n

\n

Bioavail-ability Score<\/strong><\/p>\n<\/td>\n

\n

Lead-likeness #violations<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

1<\/p>\n<\/td>\n

\n

Doxorubicin<\/p>\n<\/td>\n

\n

132.66<\/p>\n<\/td>\n

\n

0.52<\/p>\n<\/td>\n

\n

Yes<\/p>\n<\/td>\n

\n

0.17<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n<\/tr>\n

\n

2<\/p>\n<\/td>\n

\n

Daunorubicin<\/p>\n<\/td>\n

\n

131.5<\/p>\n<\/td>\n

\n

1.18<\/p>\n<\/td>\n

\n

Yes<\/p>\n<\/td>\n

\n

0.17<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n<\/tr>\n

\n

3<\/p>\n<\/td>\n

\n

Epirubicin<\/p>\n<\/td>\n

\n

132.66<\/p>\n<\/td>\n

\n

0.5<\/p>\n<\/td>\n

\n

Yes<\/p>\n<\/td>\n

\n

0.17<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n<\/tr>\n

\n

4<\/p>\n<\/td>\n

\n

Idarubicin<\/p>\n<\/td>\n

\n

125.01<\/p>\n<\/td>\n

\n

1.14<\/p>\n<\/td>\n

\n

Yes<\/p>\n<\/td>\n

\n

0.55<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n<\/tr>\n

\n

5<\/p>\n<\/td>\n

\n

Amrubicin<\/p>\n<\/td>\n

\n

120.2<\/p>\n<\/td>\n

\n

0.82<\/p>\n<\/td>\n

\n

Yes<\/p>\n<\/td>\n

\n

0.55<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n<\/tr>\n

\n

6<\/p>\n<\/td>\n

\n

Annamycin<\/p>\n<\/td>\n

\n

137.59<\/p>\n<\/td>\n

\n

0.99<\/p>\n<\/td>\n

\n

Yes<\/p>\n<\/td>\n

\n

0.17<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n<\/tr>\n

\n

7<\/p>\n<\/td>\n

\n

13-deoxy-dextrorubicin<\/p>\n<\/td>\n

\n

134.18<\/p>\n<\/td>\n

\n

0.95<\/p>\n<\/td>\n

\n

Yes<\/p>\n<\/td>\n

\n

0.17<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n<\/tr>\n

\n

8<\/p>\n<\/td>\n

\n

Esorubicin<\/p>\n<\/td>\n

\n

136.2<\/p>\n<\/td>\n

\n

1.76<\/p>\n<\/td>\n

\n

Yes<\/p>\n<\/td>\n

\n

0.55<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n<\/tr>\n

\n

9<\/p>\n<\/td>\n

\n

Zorubicin<\/p>\n<\/td>\n

\n

167.5<\/p>\n<\/td>\n

\n

2.24<\/p>\n<\/td>\n

\n

No<\/p>\n<\/td>\n

\n

0.17<\/p>\n<\/td>\n

\n

2<\/p>\n<\/td>\n<\/tr>\n

\n

10<\/p>\n<\/td>\n

\n

Mutamycine E<\/p>\n<\/td>\n

\n

132.12<\/p>\n<\/td>\n

\n

0.56<\/p>\n<\/td>\n

\n

Yes<\/p>\n<\/td>\n

\n

0.17<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n<\/tr>\n

\n

11<\/p>\n<\/td>\n

\n

Tetracycline<\/p>\n<\/td>\n

\n

110.22<\/p>\n<\/td>\n

\n

-0.56<\/p>\n<\/td>\n

\n

No<\/p>\n<\/td>\n

\n

0.11<\/p>\n<\/td>\n

\n

1<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

MR = Molar refractivity, Consensus Log P = It is method is similar (but not identical) to the ClogP method in Swiss ADME.<\/em><\/p>\n\n\n

Sixth is fail in development of the highly potent compound\n6. The full output of the in-silico<\/em> calculation of ADME (Table 4) showed\nthat compound 6 has four deviations when investigated for drug-likeness namely\nbeing alkyl halide, iodine derivative, the molecular weight, and the bone\nmarrow toxicity. <\/p>\n\n\n\n

There are several analogs related to doxorubicin appear with less side effects on heart and Table 5 introduces the comparative data between these derivatives and doxorubicin as well as between each other.119-152<\/sup> <\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 6: <\/strong>Topology G1 and G2 of doxorubicin bearing the structural units for anticancer activity and 3D-fully optimized structure of doxorubicin.<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Table 5: Comparative cardiac effects versus doxorubicin and\/or each other.<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Compound<\/strong><\/p>\n<\/td>\n

\n

Comparative cardiotoxicity<\/strong><\/p>\n<\/td>\n

\n

References \/ Findings<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Daunorubicin; Compound 2<\/p>\n

 versus doxorubicin<\/p>\n<\/td>\n

\n

By contrast, daunorubicin was approximately half as cardiotoxic when compared with doxorubicin.<\/p>\n

Daunorubicin was less cardiotoxic among survivors of childhood cancer.<\/p>\n<\/td>\n

\n

Ref  (119, 120)<\/p>\n

 <\/p>\n

1- C-9 acetyl instead of hydroxyl-acetyl<\/p>\n

2- Sugar at C-7 substituents differently arranged<\/p>\n

3- Methoxy-substituent at C-7.<\/p>\n<\/td>\n<\/tr>\n

\n

Epirubicin; Compound 3<\/p>\n

 versus doxorubicin<\/p>\n<\/td>\n

\n

Clinical trials demonstrated safety comparable to that of doxorubicin in early and advanced breast cancer. Epirubicin has been favored over doxorubicin for lower cardiac toxicity<\/p>\n<\/td>\n

\n

Ref (92, 121-123)<\/p>\n

It is the diastereomer of doxorubicin. Sugar C5\u2019 alpha-hydroxyl group.<\/p>\n

1- C-9 acetyl instead of hydroxyl-acetyl<\/p>\n

2- Sugar at C-7 substituents differently arranged<\/p>\n

3- Methoxy-substituent at C-7.<\/p>\n<\/td>\n<\/tr>\n

\n

Idarubicin; Compound 4<\/p>\n

 versus doxorubicin<\/p>\n

 <\/p>\n<\/td>\n

\n

It is more cytotoxic than doxorubicin, explained by higher hepatic penetration because of high lipophilicity.<\/p>\n

Orally active. It is less cardiotoxic than doxorubicin in phase II clinical trials.<\/p>\n<\/td>\n

\n

Ref (124) & Ref. (92, 100, 125-127)<\/p>\n

 <\/p>\n

1- C-9 acetyl instead of hydroxyl-acetyl<\/p>\n

2- Amino-sugar at C-7.<\/p>\n

3- No substituent at C-4.<\/p>\n<\/td>\n<\/tr>\n

\n

Idarubicin; Compound 4<\/p>\n

 vesus Epirubicin<\/p>\n<\/td>\n

\n

A significantly lower accumulation in cardiomyocytes was obtained with epirubicin and idarubicin compared with carminomycin and doxorubicin.<\/p>\n<\/td>\n

\n

Ref. (126-129)<\/p>\n

1- C-9 acetyl instead of hydroxyl-acetyl<\/p>\n

2- Amino-sugar at C-7.<\/p>\n

3- No substituent at C-4.<\/p>\n<\/td>\n<\/tr>\n

\n

Esorubicin; Compound 11<\/p>\n

 (CLogP: 0.879) versus doxorubicin<\/p>\n<\/td>\n

\n

For human solid tumors in vitro in clonogenic assay appeared to be more potent on a weight basis than DOX.<\/p>\n

ESO has been reported to have decreased cardiac toxicity in preclinical models as compared to DOX.<\/p>\n<\/td>\n

\n

Ref. (130-132)<\/p>\n

Experimental<\/p>\n

1- C-9 hydroxyl-acetyl, similar<\/p>\n

2- Deoxy-sugar at C-7 substituents (a hydroxyl group is missed from the C-7 entity)<\/p>\n

3- Methoxy-substituent at C-7, similar<\/p>\n<\/td>\n<\/tr>\n

\n

Amrubicin; Compound 5<\/p>\n

 versus doxorubicin<\/p>\n

 <\/p>\n

N.B. Not approved FDA but approved in Japan<\/p>\n<\/td>\n

\n

There was no significant cardiac toxicity, and concluded that amrubicin has efficacy
comparable to doxorubicin<\/p>\n

Amrubicin showed lower cardiotoxicity at equivalent dosages. This seems to be due to the restricted distribution of the active metabolite in non-tumor tissues.<\/p>\n<\/td>\n

\n

Ref (133, 134), (58, 135)<\/p>\n

 <\/p>\n

1- C-9 acetyl instead of hydroxyl-acetyl<\/p>\n

2- No amino group and no methyl group in the sugar at C-7.<\/p>\n

3- No substituent at C-4.<\/p>\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Annamycin; Compound 6<\/p>\n

 versus doxorubicin<\/p>\n<\/td>\n

\n

Annamycin have little to no cardiac toxicity. It is formulated in a nano-molecular bi-lamellar liposomal system.<\/p>\n

Side effect (136)<\/p>\n

Bone marrow toxicity delaying its development.<\/p>\n<\/td>\n

\n

Ref (137), (62), (63, 136, 137)<\/p>\n

1- C-9 hydroxyl-acetyl<\/p>\n

2- Sugar at C-7 the substituents with iodine and no amino group.<\/p>\n

3- No substituent at C-7.<\/p>\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Zorubicin; Compound 12<\/p>\n

 versus doxorubicin<\/p>\n<\/td>\n

\n

Toxicity appears high grade granulo-cytopenia, thrombo-cytopenia,<\/p>\n

 <\/p>\n

Cardiotoxicity appears like DOX.<\/p>\n<\/td>\n

\n

Ref (138-141)<\/p>\n

 <\/p>\n

It is the phenylhydrazone of daunorubicin.<\/p>\n

1- C-9 acetyl instead of hydroxyl-acetyl<\/p>\n

2- Amino-sugar at C-7.<\/p>\n

3- Methoxy substituent at C-4.<\/p>\n<\/td>\n<\/tr>\n

\n

Amsacrine; Compound 7<\/p>\n

 versus doxorubicin<\/p>\n<\/td>\n

\n

Amsacrine in clinical trials it developed occasional instances of acute cardiac arrhythmias and cardiomyopathy. Amsacrine-related cardiac events are less common than those related to anthracycline chemotherapeutic agents.<\/p>\n<\/td>\n

\n

Ref. (142-146)<\/p>\n

Acridine derivative<\/p>\n

 <\/p>\n

 <\/p>\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Pixantrone; Compound 8<\/p>\n

 versus doxorubicin<\/p>\n<\/td>\n

\n

It is of reduced cardiotoxic potential compared with doxorubicin and mitoxantrone<\/p>\n<\/td>\n

\n

Ref. (66, 67, 147, 148)<\/p>\n

Benzo(g)isoquinoline derivative<\/p>\n

 <\/p>\n<\/td>\n<\/tr>\n

\n

Mitoxantrone; Compound 9; versus doxorubicin<\/p>\n<\/td>\n

\n

Active DNA intercalating agent with low cardiotoxic potential.<\/p>\n<\/td>\n

\n

Ref. (125, 149-151)<\/p>\n

Aza-anthraquinone derivative<\/p>\n<\/td>\n<\/tr>\n

\n

SP1049C; Compound 13; doxorubicin in P-glyco-protein versus doxorubicin<\/p>\n

 <\/p>\n<\/td>\n

\n

P-glycoprotein for increasing cellular uptake, transport, and half-lives of drugs. It is not approved, yet. It reduces the relative cardiotoxity to about half of that of doxorubicin.<\/p>\n<\/td>\n

\n

Ref. (126, 127, 152, 153)<\/p>\n

 <\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Conclusion<\/strong><\/p>\n\n\n\n

Anthracyclines have showed a great deal of cytotoxic activity since\ntheir incorporation in cancer treatment protocols, with considerable attempts\nto ameliorate their structure to overcome their evident cardiotoxicity. The\napproaches towards making better anthracyclines as anticancer agents are slow.\nIn this work the structures of drugs in clinical use, the orphan drugs, the\ncandidates bearing high cytotoxic activity and examples of tetracyclic\nstructures bearing weak and\/or cytotoxicity are collected for investigation.\nImportant findings have been introduced in different points around the\ntopological 3D-feature (Figure 6). Taking in consideration the points mentioned\nabout the substitutions around main tetracyclic structure may help in\nintroducing a selective and potent anticancer with much less cardiotoxicity\nfrom anthracycline-scaffold which still very important in treatment of solid\ntumors.<\/p>\n\n\n\n

Acknowledgement<\/strong><\/p>\n\n\n\n

The\nauthors would like to acknowledge University\nof Sharjah, Sharjah, United Arab Emirates. <\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

The\nauthor(s) received no financial support for the research, authorship, and\/or\npublication of this article <\/strong><\/p>\n\n\n\n

Conflicts\nof Interest<\/strong><\/p>\n\n\n\n

The authors do not have any conflict\nof interest.<\/p>\n\n\n\n

Ethical\nApprovals<\/strong><\/p>\n\n\n\n

This research did not involve human participants, animal subjects, or\nany material that requires ethical approval<\/p>\n\n\n\n

Authors\u2019\nContributions<\/strong><\/p>\n\n\n\n

All authors made a significant and equal contribution to\nthis work.<\/p>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

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