From COX-2 Inhibitor Nimesulide to Potent Anti-Cancer Agent: Synthesis, in Vitro, in Vivo and Pharmacokinetic Evaluation

Cleveland State University EngagedScholarship@CSU Chemistry Faculty Publications Chemistry Department 1-1-2012 From COX-2 Inhibitor Nimesulide to Potent Anti-Cancer Agent: Synthesis, In Vitro, In Vivo and Pharmacokinetic Evaluation Bo Zhong Cleveland State University Xiaohan Cai Cleveland State University Snigdha Chennamaneni Cleveland State University Xin Yi Cleveland State University Lili Liu Case Western Reserve University See next page for additional authors Follow this and additional works at: https://engagedscholarship.csuohio.edu/scichem_facpub Part of the Medicinal-Pharmaceutical Chemistry Commons How does access to this work benefit ou?y Let us know! Recommended Citation Zhong, Bo; Cai, Xiaohan; Chennamaneni, Snigdha; Yi, Xin; Liu, Lili; Pink, John J.; Dowlati, Afshin; Xu, Yan; Zhou, Aimin; and Su, Bin, "From COX-2 Inhibitor Nimesulide to Potent Anti-Cancer Agent: Synthesis, In Vitro, In Vivo and Pharmacokinetic Evaluation" (2012). Chemistry Faculty Publications. 196. https://engagedscholarship.csuohio.edu/scichem_facpub/196 This Article is brought to you for free and open access by the Chemistry Department at EngagedScholarship@CSU. It has been accepted for inclusion in Chemistry Faculty Publications by an authorized administrator of EngagedScholarship@CSU. For more information, please contact [email protected]. Authors Bo Zhong, Xiaohan Cai, Snigdha Chennamaneni, Xin Yi, Lili Liu, John J. Pink, Afshin Dowlati, Yan Xu, Aimin Zhou, and Bin Su This article is available at EngagedScholarship@CSU: https://engagedscholarship.csuohio.edu/scichem_facpub/196 432 433 shown to protect against N nitrosobis(2 oxopropyl)amine induced mixture was stirred at room temperature overnight to obtain the pancreatic tumors in hamster [32]. In some in vitro experiments, N,N bimethanesulfonamido b. Compound b was hydrolyzed with nimesulide is able to inhibit the proliferation and to increase the 10% NaOH solution to generate c as a monomethanesulfonamido apoptosis rate of various types of cancer cells [18,25,33e38]. compound. Compound c was treated with sodium hydride and However, the nimesulide concentrations used in these studies are methyl iodine in DMF at room temperature to obtain compound d. ranged from 200 to 500 mM, which greatly exceed the concentra Then the nitro group was reduced to an amine group to obtain tion necessary to inhibit COX 2 activity. These facts suggest that compound e. Compound e was treated with different substituted nimesulide inhibits cancer cell growth and induces cancer cell acetyl chloride and K2CO3 to generate the substituted benzamides apoptosis independent of COX 2. 1e39, respectively. Structures of all the synthesized compounds JCC76 is a non COX 2 active nimesulide analog (Fig. 1) [39e41], were determined by 1H NMR, MS, and their purity was confirmed and it inhibits SKBR 3 breast cancer cell growth with an IC50 of by HPLC with two mobile phases. 1.38 mM, which is about 100 fold more active than nimesulide (Table 1). The N Methylation of JCC76 blocks the ionization of the Biological evaluation of the new analogs with breast cancer cell sulfonamide group, which abolishes the potential COX 2 activity line SKBR 3 [42e44]. In addition, the aromatic nitro group is converted to an amide moiety on the structure of JCC76, which could diminish the The compounds were tested for the inhibition of SKBR 3 breast potential hepatotoxicity, since nimesulide shows hepatotoxicity cancer cell growth (Table 1). Subsequently, a detailed structure due to the multistep nitroreductive bioactivation that produces the activity analysis was performed based on the structure and the hazardous nitroanion radical and nitroso intermediate [45]. Based anti cancer activity. The new derivatives have same core structure on the structure of JCC76, more analogs were designed and as JCC76, the different activity is correlated with the different amide synthesized in the current studies. Some new analogs such as moieties. CSUOH0901 (NSC751382) inhibited SKBR 3 breast cancer cell For the substituted benzamide moiety in the structure, para m e m growth with IC50s around 0.1 M 0.2 M, which is about 10 fold position bulky halogen substituted benzamide such as 9 (bromine) more active than JCC76 and almost 1000 fold more active than with an IC50 of 0.22 mM and 29 (iodine) with an IC50 of 0.13 mM nimesulide. In addition, CSUOH0901 inhibited the growth of show better potency than JCC76, whereas small halogen chlorine at a broad range of cancer cell lines with IC s of 0.2 mM to 0.5 mM. It 50 para position (28) slightly decreases the activity with an IC50 of also inhibited the growth of HT29 colorectal xenograft in nude mice 2.15 mM. It is also possible that the activity is related to the elec as well. All the studies suggest that the newly developed JCC76 tronegativity or electron density of the halogens. Iodine has the derivatives are promising anti cancer drug candidates. lowest electronegativity and highest electron density, which may contribute to the potent anti cancer activity. 2, 8, 25, 20, and 27, Results and discussion which have single meta substitution groups, display weaker inhibitory activity with IC50s ranging from 1.97 mM to 7.34 mM. It Compound design and parallel synthesis of JCC76 derivatives seems that single meta substitution is predominated by steric effect. The activity is decreased no matter the substitution is In previous studies, systematic modification was performed on electron donating or withdrawing group. Dual chlorine substitu the structure of nimesulide to improve the anti cancer activity and tion (4 and 14) slightly increases the activity compared to JCC76, erase the COX 2 inhibitory activity [41,46]. SAR result suggests that with IC50 of 0.91 mM and 0.80 mM respectively. 1, 2, 3, 7, 8, 15, 21 and the dimethyl benzyl and methylsulfonamide moieties are critical 34, which have electron withdrawing groups as substitution, for the nimesulide analogs to inhibit cancer cell growth (Fig. 1). exhibit IC50s among 1.0 mMe3.0 mM. The results suggest that Further, the conversion of the nitro group to a bulky amide moiety electron withdrawing groups such as nitro, cynao, multi fluoro, generated novel anti cancer agent JCC76 [39e41,46]. In the current and trifluoro methyl substituted benzamide do not increase the study, dimethyl benzyl and methylsulfonamide groups which are activity. 26 shows very weaker activity with an IC50 of 55.35 mM, important for the anti cancer activity of the derivatives were which possibly is due to the very strong electron withdrawing maintained, and we focused on the modification of the amide effect and the meta position steric effect of the di trifluoro moiety of JCC76. Various chemical structures including alkyl amide methyl groups. Most of the strong electron donating groups such groups, electron donating or withdrawing group substituted ben as methoxyl and multi methoxyl substituted benzamide (10, 11, 16, zamides, bulky or small group substituted benzamides, and 18 and 19) increase the activity with IC50s among 0.19 mMe0.68 mM. heterocyclic amides were introduced at this moiety. However, para methyl benzamide (33) and para ethyl benzamide The synthesis is described in Scheme 1. The starting material 2 (36) show lesser potency with IC50s of 2.48 mM and 2.82 mM amino 5 nitrophenol was refluxed with K2CO3 and 2, 5 dimethyl respectively, although both methyl and ethyl groups are electron benzyl chloride to obtain compound a. Sodium hydride and donating substitution. It suggests that para position steric effect methanesulfonyl chloride were added to compound a in dry reduces the activity, but strong electron donating group at para dimethylformamide (DMF) at room temperature and the reaction position overall increase the activity because the electron donating H O N O O N O H 2 O N O NH N N O S O O S O O S O O JCC76 Nimesulide O First generation of Nimesulide CSUOH0901 analog as anti-cancer agent Second generation Fig. 1. Anti-cancer drug development based on COX-2 inhibitor nimesulide. 434 Table 1 Table 1 (continued ) Inhibition of cancer cell growth of the JCC76 anlogs. Entry H IC50 against Entry IC50 against H N O SKBR-3 breast N O SKBR-3 breast R cancer cell growth R cancer cell growth N N O S O O S O O O CF3 Æ m JCC76 R= 1.38 Æ 0.10 mM 15 R= 2.78 0.29 M O O R= 1 1.13 Æ 0.10 mM OCH3 16 R= 0.19 Æ 0.14 mM NO2 OCH3 O OCH NO 3 2 R= 2 1.97 Æ 0.21 mM R= 17 34.02 Æ 2.01 mM O OCH3 O O R= NO2 R= 3 3.35 Æ 0.40 mM 18 0.15 Æ 0.05 mM Cl OCH3 O O OCH Cl 3 4 R= 0.91 Æ 0.05 mM 19 R= 0.68 Æ 0.32 mM Cl O O 5 R= 0.21 Æ 0.01 mM OCH 20 R= 3 6.88 Æ 3.18 mM O O F R= Æ m 6 2.28 0.09 M R= OCH3 21 2.16 Æ 1.08 mM F O F 7 R= 1.46 Æ 0.06 mM O CN 22 R= 51.24 Æ 4.49 mM O O CN 8 R= 3.01 Æ 0.12 mM 23 R= 11.21 Æ 4.47 mM O R= 9 0.22 Æ 0.01 mM R= 24 >100 mM Br O O O 10 (CSUOH0901; R= O 0.20 Æ 0.01 mM R= NSC751382) 25 3.95 Æ 2.09 mM O O R= OCH3 O 11 0.30 Æ 0.02 mM CF 3 OCH3 R= 26 55.35 Æ 4.11 mM OCH3 O O CF3 12 43.27 Æ 7.38 mM R= Br 27 R= 7.34 Æ 3.99 mM O 13 R= 11.05 Æ 4.76 m3M 14 O 2.15 Æ 0.94 mM O 28 R= 14 0.80 Æ 0.01 mM R= Cl Cl Cl 435 Table 1 (continued ) effect of meta substitution.

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