Anticancer activity oF the selected dipyridothiazines and
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Anticancer activity oF the selected dipyridothiazines and
&ARM0RZEGL.AUK !NTICANCERACTIVITYOFTHESELECTEDDIPYRIDOTHIAZINES ANDDIQUINOTHIAZINESDETERMINEDIN.ATIONAL#ANCER)NSTITUTE IN"ETHESDA53! !KTYWNOu¿PRZECIWNOWOTWOROWAWYBRANYCHDIPIRYDOTIAZYN IDICHINOTIAZYNZBADANAW.ATIONAL#ANCER)NSTITUTEW"ETHESDZIE53! +RYSTIAN0LUTA-AGORZATA*ELEÊ"EATA-ORAK-ODAWSKA 4HE-EDICAL5NIVERSITYOF3ILESIA$EPARTMENTOF/RGANIC#HEMISTRY 3OSNOWIEC0OLAND Abstract Seventeen selected newly synthesized azaphenothiazines, being tricyclic 10-substituted dipyridothiazines A1-A8 and pentacyclic 6-substituted diquinothiazines B1-B9 were investigated in vitro against the cell lines of 9 types of human cancer: leukemia, melanoma, non-small cell lung cancer, colon cancer, CNS cancer, ovarian cancer, renal cancer, prostate cancer and breast cancer in National Cancer Institute, Bethesda, USA. This study showed that the cell lines of all 9 cancer types were sensitive to our compounds. Two dipyridothoazines A and all diquinothiazines B were active against at least one cancer cell line. Pentacyclic quinothiazines B were much more active than tricyclic dipyridothiazines A. To our knowledge this study is a first demonstration of significant anticancer activities of azaphenothiazines. Key words: phenothiazines, azaphenothiazines, dipyridothiazines, diquinothiazines, anticancer activity Introduction Phenothiazines are significant class of heterocyclic compounds for their interesting chemical properties and widely recognized pharmacological activity (neuroleptic, antihistaminic, antitussive and antiemetic [1]). Recent reports demonstrated promising anticancer [2, 3], antiplasmid [4] and antibacterial activities [5], reversal of multidrug resistance (MDR) [6, 7] and potential treatment in Alzheimer’s [8], Creutzfeldt-Jakob [9] and AIDS diseases [10] of typical and newly synthesized phenothiazines. Significant anticancer activity was found not only for typical neuroleptic phenothiazines but also for new phenothiazine derivatives [11-13] which were obtained by introduction of new pharmacophoric groups at the thiazine nitrogen atom Streszczenie Siedemnaście wybranych ostatnio otrzymanych azafenotiazyn, będących tricyklicznymi 10-podstawionymi dipirydotiazynami A1-A8 i pentacyklicznymi 6-podstawionymi dichinotiazynami B1-B9 zostało przebadanych in vitro na liniach komórkowych 9 typów ludzkiego nowotworu: białaczki, czerniaka, nowotworów płuc, okrężnicy, centralnego układu nerwowego, jajnika, nerki, prostaty i piersi w National Cancer Institute w Bethesdzie, USA. Badania wykazały, że linie komórkowe wszystkich 9 typów nowotworów były wrażliwe na nasze związki. Dwie dipirydotiazyny A i wszystkie dichinotiazyny B były aktywne w stosunku do co najmniej jednej linii komórek nowotworowych. Pentacykliczne dichinotiazyny B były bardziej aktywne niż tricykliczne dipirydotiazyny A. Według naszej wiedzy przedstawione badania są pierwszym przykładem znaczących aktywności przeciwnowotworowych azafenotiazyn. Słowa kluczowe: fenotiazyny, azafenotiazyny, dipirydotiazyny, dichinotiazyny, aktywność przeciwnowotworowa and by substitution of the benzene ring with the naphthalene ring to form benzophenothiazines and dibenzothiazines. We modified the phenothiazine structure with the pyridine and quinoline rings to form new azaphenotiazines being 10-substituted dipyridothiazines (10-substituted 2,7diazaphenothiazines) and 6-substituted diquinothiazines (6-substituted dibenzo-1,9-diazaphenothiazines). Some of these compounds exhibit very significant anticancer activity determined in National Cancer Institute in Bethesda, USA. The most active turned out to be 6-chloroethylureidoethyldiquinothiazine with growth inhibition GI50 = 0.04 μg/ml (40 ng/ml) against melanoma line SK-MEL-5 [14]. In this paper, we demonstrate the anticancer activity of less active dipyridothiazines A1-A8 and diquinothiazines B1-B9 COPYRIGHT'RUPADR!2+WIECIÊSKIEGO)33. determined against cancer cell lines in order to discuss the structure-activity relationship and to search for effective anticancer drugs. Materials and methods Chemicals 10-Substituted tricyclic dipyrido[3,4-b;3’,4’-e][1,4]thiazines A1-A8 and 6-substituted pentacyclic diquino[3,2b;2’,3’-e][1,4]thiazines B1-B9, depicted in Fig. 1, were synthesized according to the recently described procedures [15-18]. These compounds possess the alkyl, aryl, heteroaryl, N,N-dialkylaminoalkyl, N-acylaminoalkyl and N-sulfonylaminoalkyl groups at the thiazine nitrogen atom. Assay for anticancer activity The anticancer activity parameter such as the percentage of growth (PG in %) of azaphenothiazines A1-A8 and B1-B9 was determined by the dose-response curve using the cell lines of 9 types of human cancers (leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer cell lines) at concentration of 10-5 M/l in National Cancer Institute (Bethesda) in Vitro Anticancer Drug Discovery Screen Program [19]. Azaphenothiazines which give lower PG value are considered as more potent anticancer compounds. Results and discussion The anticancer activities of dipyridothiazines A1-A8 and diquinothiazines B1-B9, as the PG values, were shown in Tables 1 and 2, respectively. To short this review, the discussion was limited to those compounds which exhibit the PG values below or around 60% and to 28 cancer cell lines. As one can see from Tables diquinothiazines B1-B9 turned out to be more active than dipyridothiazines A1-A8. Below, R N N A2. Anti-breast cancer activity 4 Diquinothiazines (B1,B3, B6 and B8) were found active against MCF7 line and 3 diquinothiazines (B1, B8 and B9) against T-47D line, 2 diquinothiazines (B5 and B7) against MDA-MB231/ATCC line and diquinothiazines B7 against HS578T line. Dipyridothiazine B1 showed activity against HS578T line. Compound B1 showed the most potent activity with the remarkable PG values of 7 % and 14%. Anti-leukemia activity Diquinothiazine B3, B4 and B8 exhibit activity against SR line. Anti-renal cancer activity It is worth noting that all diquinothiazines (B1-B9) and 2 dipyridothiazine (A1 and A2) exhibit potent activity against UO-31 line. The most active was compound B6 with the PG value of 19%. Anti-melanoma activity 6 Diquinothiazines (B1, B2, B4-B6 and B8) showed activity against SK-MEL2 line and diquinothiazine B8 against UACC-62 line. Anti-colon cancer activity Diquinothiazines B1 and B8 exhibited activity against KM12 and HCT-116 lines, respectively. N N R N N S NO2 N R NSC No 743522/1 B1. -CH2CH2CH2CH3 743518/1 B2. O2N H3C H3C Anti-non-small cell lung cancer activity Whereas only dipyridothiazine A1 and diquinothiazines B5 were active against EKVX line, 6 diquinothiazines (B1, B4, B5, B7-B9) were found active against HOP-92 line. Some other compounds were only a little less active. S R A1. -CH3 A3. there is short review of antiproliferative activities against the cell lines of 9 types human cancers. CH2 NSC No 744651/1 744654/1 B3 Cl 744652/1 B4.. NO2 744653/1 743523/1 N A4.. N N 743524/1 B5. Cl O A5. -CH2CH2CH2 N 743521/1 O A6. -CH2CH2N(C2H5)2 743519/1 A7. -CH2CH(CH3)CH2N(CH3)2 743525/1 A8. -CH2CH2CH2NHCOCH3 743520/1 744655/1 N B6. -CH2CH2NHCOCH3 B7. -CH2CH2CH2NHCOCH3 B8. -CH2CH2CH2NHCOOC2H5 B9. -CH2CH2CH2NHSO2C6H4CH3 744657/1 744661/1 744663/1 744662/1 Fig. 1. Structures of dipyridothiazines A1-A8 and diquinothiazines B1-B9 with National Cancer Institute code numbers &ARM0RZEGL.AUK Tab. I. Anticancer activity (PG in % at concentration of 10-5 M) of dipyridothiazines A1-A8 Non-small cell Compd’s lung cancer number HOP-92 NCI-H522 EKVX HS578T A1 A2 A3 A4 A5 A6 A7 A8 49 89 79 >90 >90 >90 >90 >90 64 >90 >90 >90 >90 >90 >90 >90 85 80 77 90 >90 89 87 90 >90 88 73 >90 >90 90 90 78 Renal cancer Compd’s number RXF-393 A1 A2 A3 A4 A5 A6 A7 A8 >90 84 >90 >90 >90 >90 >90 >90 Melanoma Compd’s number UACC-62 A1 A2 A3 A4 A5 A6 A7 A8 >90 >90 81 >90 >90 >90 87 >90 Breast cancer Leukemia MDA-MB231-ATCC 90 77 85 >90 >90 >90 >90 85 K-562 RPMI-822 >90 87 83 >90 89 >90 >90 >90 >90 >90 86 >90 >90 >90 88 >90 Ovarian cancer CNS Cancer UO-31 ACHN OVCAR-8 SNB-75 SF-295 40 56 >90 - >90 >90 75 >90 >90 >90 >90 >90 >90 87 83 90 >90 >90 >90 >90 85 >90 >90 90 87 89 >90 83 >90 >90 87 >90 >90 88 >90 >90 Prostate cancer Colon cancer U251 PC-3 COLO 205 >90 >90 88 >90 >90 >90 >90 >90 >90 88 >90 >90 >90 >90 >90 >90 >90 >90 90 >90 >90 >90 >90 >90 Anti-ovarian cancer activity Diquinothiazine B7 showed activity against SK-OV-3 line. Anti-CNS cancer activity Diquinothiazine B7 was found to be active against U251 and SNB-75 lines. Anti-prostate cancer activity Diquinothiazine B8 showed activity against PC-3 line. This short commentary demonstrates anticancer potential and selectivity of our new azaphenothiazines. Some compounds exhibited significant antiproliferative activity, for example compounds B1, B6, B5, B8 and B7 against the selected cell lines (Table 2). It worth noting that less active dipyridothoazines A showed antiproliferative activity against to the selected cancer lines with the PG values of 40-90% (Table 1). Taking into account the phenothiazine structures A and B, it seems that the multicyclic ring system is much more biological potent than the nature of the pharmacophoric substituents. Tab. II. Anticancer activity (PG in % at concentration of 10-5 M) of diquinothiazines B1-B9 Compd’s number B1 B2 B3 B4 B5 B6 B7 B8 B9 Compd’s number B1 B2 B3 B4 B5 B6 B7 B8 B9 Non-small cell lung cancer HOP-92 HOP-62 28 >90 73 84 90 62 80 39 >90 75 89 47 69 49 76 69 >90 R e n a l Melanoma cancer Breast cancer EKVX MCF7 HS578T 85 >90 >90 >90 69 86 86 74 72 7 61 37 >90 74 53 60 45 70 >90 89 88 85 83 >90 63 82 >90 Leukemia MDA-MB231/ ATCC 76 >90 >90 84 68 80 66 77 83 T-47D SR 14 >90 77 89 83 80 83 39 64 77 81 65 54 78 87 80 44 83 Colon cancer Ovarian cancer CNS cancer Prostate cancer UO-31 SK-MEL2 UACC-62 KM12 HCT-116 SK-OV-3 SNB-75 U251 PC-3 22 39 43 37 27 19 29 24 32 62 67 78 64 39 63 76 62 71 >90 85 85 77 78 >90 78 59 76 68 >90 >90 >90 >90 >90 82 - >90 >90 85 90 >90 >90 87 68 >90 >90 >90 >90 >90 >90 >90 65 88 >90 >90 >90 >90 >90 >90 >90 60 >90 >90 >90 >90 >90 >90 86 >90 57 >90 >90 79 >90 81 73 86 75 67 82 COPYRIGHT'RUPADR!2+WIECIÊSKIEGO)33. Conclusions This study showed that the cell lines of all 9 cancer types were sensitive to our compounds. Two dipyridothoazines A and all diquinothiazines B were active against at least one cancer cell line. Pentacyclic quinothiazines B were much more active than tricyclic dipyridothiazines A. To our knowledge this study is a first demonstration of significant anticancer activities of azaphenothiazines. References 1. Gupta RR and Kumar M. Synthesis, properties and reactions of phenothiazines. In: Gupta, RR (ed) Phenothiazines and 1,4-Benzothiazines. Chemical and Biological Aspects. Elsevier, 1988, 1-161. 2. Motohashi N et al: Antitumor potential and possible targets of phenothiazine-related compounds. Curr Drug Targets 2000; 1: 237-245. 3. Motohashi N et al: Cytotoxic potential of phenothiazines. Curr Drug Targets 2006; 7: 1055-1066. 4. Molnár A, Amaral L, Molnár J. Antiplasmid effect of promethazine in mixed bacterial cultures. Int J Antimicrob Agents 2003; 22: 217-222. 5. 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Acyl and sulfony derivatives of 10-aminoalkyl-2,7-dia-zaphenothiazines. Heterocycles, 2009;7 8: 1289-1298. 18. Jeleń M, Pluta K. Synthesis of 6-aminoalkyldiquino-1,4-thiazines and their acyl and sulfonyl derivatives. Heterocycles, 2008; 75: 859-870. 19. Shoemaker RH. The NCI human tumor cell line anticancer drug screen. Nature Rev, 2006; 6: 813-823. Address for correspondence: dr hab. Krystian Pluta The Medical University of Silesia Department of Organic Chemistry Jagiellońska 4, 41-200 Sosnowiec, Poland e-mail: [email protected].