Study on the Redox Metabolism Mechanism of Aclacinomycin2A

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1 ACTA CHIMICA SINICA Vol No A Ξ Ξ ( ) 2A 2A 2A ph 72 Study on the Redox Metabolism Mechanism of Aclacinomycin2A CHENG Gui2Fang DING Min ZHAO Jie HE Pin2Gang FANG Yu2Zhi Ξ ( Department of Chemistry East China Normal University Shanghai ) Abstract Aclacinomycin with high eutherapeuticity and low toxicity is a new compound of anthacyclines when the application of other anthracycline drugs in therapeutics is heavily restricted by their high toxicity Up to now it is still a question of antitumor action of ACM and its low toxicity Antitumor activity cardiotoxicity and cytotoxicity of these kinds of medicine are closely related to their redox behavior in vivo In this work an investigation of the redox mechanism of ACM2A in simulated metabolic process was made and a possible reduction mechanism of ACM2A was proposed : ACM2A is able to get two electrons becoming hydroaclarimycinone2a then partly goes on a deaglycone to form 72deoxyaclarimycinone in neutral and alkaline media Two of 72deoxyaclarimycinone can associate As no semiquinone free radicals are produced in reduction and no free radical chain reaction exists to cause the damage of mitochondria DNA in heart and other cells with low cardiotoxicity and cytotoxicity ACM2A has wilder application in clinical Another result obtained in this work is that the reduction of anthracycline drug and side effect in therapy was correlated to its aglycone structure The results obtained offered new method for medical design and selection Keywords aclacinomycin metabolic mechanism anthracycline spectroelectrochemistry Laine [2] ACM ( II) G1 ;Nabiev [3] ACM2A Santopin ACM2A (ACM) Streptomyces galilaeus ( ) DNA DNA ( 1) C O ;Tanaka [4] ADM (ADM) (DNR) DRN ACM X174 DNA [1] ACM ACM X174DNA Cu 2 + Ξ E2mial : sh cn Received October ; revised February ; accepted March (No )

2 1300 Vol Figure 1 The structure of anthracyclines X174 DNA CHI660 ( CHI ) Cary50 SOD ; Utsuno [5] - ( ) JASCO2J20C ACM DNA DNA ( ) ZF23 ( ) DNR ; Junping [6] ACM (1 cm) E E2ACM 1 2 E2ACM E2ACM ACM Ag/ AgCl ( KCl) ACM ACM CV ADM DNR Kleyer [7] ACM ACM ( V) 72 ; Baldt [8] ; ACM2A 72 ACM ACM 2 1 ACM2A V ACM2A P c1 ( E Pc1 = V) P c2 ( E Pc2 = V) P a ACM2A ( E Pa = V) P c1 ( 2) P c1 P c2 P a ( V/ s) ACM2A ( ) ph = 710 PBS ( nm ( = V/ s) ; i Pa / i Pc L/ mol cm) ( > 1 V/ s) 1 ; Anson [10] ACM2A [9] ( 1) P c1 P c2

3 No 14 : 2A 1301 (ph = 310) ACM2A P c2 P a CV P c1 i Pa / i Pc 1 E p = ; i Pc V (011 V/ s) ACM2A i Pc2 ; i Pc1 v i Pc2 v 1/ 2 P c1 ph = 910 P c1 i Pa / i Pc2 ; P c2 ACM2A [11] V c ACM2A = mol/ L i Pa / i Pc2 ( 2) ACM2A 2 2 ACM2A ACM2A ACM2A ACM2A CD ( 3 a) 224 nm K K 2 3 ;270 nm B 2 3 ;328 nm R n2 3 ; 396 nm 464 nm ACM2A CD 224 nm 2 ACM2A Figure 2 Cyclic voltammogram of ACM2A in tris2hcl phosphate 270 nm 281 nm 464 nm 530 nm buffer (ph = 7 0) with scanning rate of 0 1 V/ s from to ACM2A Scan rate/ (V s - 1 ) 1 ACM2A Table 1 The cyclic voltammogram parameters of ACM2A (ph = 7 0) Cathodic wave i Pc / A E Pc1 / V i Pc / A E Pc2 / V Anodic wave i Pa 10 6 / A E Pa / V ACM2A Table 2 The cyclic voltammogram parameters of ACM2A at ph = 3 0 and ph = 9 0 Scan rate/ (V s - 1 ) E Pc / V ph = 3 0 (NaAc2HAc buffer) i Pc 10 5 / A E Pa / V i Pa 10 5 / A ph = 9 0 (phosphate buffer) E Pc / V i Pc 10 5 / A E Pa / V i Pa 10 5 / A

4 1302 Vol ACM2A Figure 3 Circular dichroism spectra of ACM2A in physio2medium ph = 7 3 (a) open circular (b) V applied for 25 min V applied for (c) 0 1 min (d) 3 min (e) 59 min c ACM2A = mol/ L ACM2A - ACM2A ACM2A nm ( 4 a) V ( ) ACM2A mol/ L) CV ( 4 b c) V nm ( 4 d e) 410 nm 2A ACM2A ( 4 f) nm 465 nm( 4 g) nm nm V ACM2A ACM2A n = 1194 P c2 ACM2A ( E o ) V (vs1 Ag/ AgCl) 410 nm 2A ph = nm nm ; ph = nm nm 470 nm ACM2A 2A [12] Zn 2 + Zn ( c + Zn = mol/ L c ACM2A = 710 ; ACM2A nm 2A 2A = mv i Pa ACM2A 434 nm ; (72 ) nm 465 nm 3 4 ACM2A - Figure 4 UV2visible spectra of ACM2A in physiomedium ph = 7 3 c ACM2A = mol/ L (a) open circuit V applied for (b) 1 0 min and (c) 60 min V applied for (d) 0 1 min (e) 1 min (f) 3 min and (g) 120 min ACM2A ACM2A : ACM2A 2A 2A 72 ; ( ) ACM2A 2A ACM2A ACM2B 3 ACM2A 5

5 No 14 : 2A ACM2A Figure 5 The metabolism scheme of ACM2A ACM DNR [9] ADM [13] ACM 3 Nabiev I ; Chourpa I ; Manfait M J Phys Chem ACM 4 Tanaka A ; Morita J ; DNR ADM Komano T Agric Biol Chem ACM ADM DNR 5 Utsuno K ; Tsuboi M Chem Pharm Bull DNA 6 Junping W J Pharmaceutics ; DNA DNA 7 Kleyer D L ; Gaudiano G ; Koch H J Am Chem Soc DNA 8 Boldt M ; Gaudiano G ; Koch T H J Org DNA Chem Qu H2Y ; Cheng G2F ; Peng H2Q ; He P2G ; Fang Y 2Z Chem J Chin Univ (in Chinese) ( ) 10 Anson F ; Huang H2Z ; Gao X2X Electrochemistry and References 1 Kim H S ; Kim Y H ; Yoo O J ; Lee J J Biosci Biotechnol Biochem Laine A ; Halo L ; Rgty K ; Kunnai T ; Mgntsglg P ; Ylihonko K Eur J Cancer (Suppl ) S117 Electroanalytical Chemistry Beijing Universiey Publisher Beijing 1983 pp (in Chinese) (Anson F 1983 pp ) 11 Anson F ; Huang H2Z ; Gao X2X Electrochemistry and Electroanalytical Chemistry Beijing Universiey Publisher Beijing 1983 pp (in Chinese)

6 1304 Vol (Anson F ; 13 Fen M ; Yang Y2L ; He P2G ; Fang Y2Z Chem J 1983 pp ) 12 Fang Y2Z ; Jiang J 2C Chin J Anal Chem (in Chinese) ( ) Chin Univ (6) 866 (in Chinese) ( (6) 866 ) (A LU Y J ; DONG H Z )

7 Graphical Abstract Vol Quantum Chemical Calculations on the Hydration and Association of MgCl 2 and CaCl 2 Solutions at High and Supercritical Temperatures DING Hao ; ZHU Yu ; WANG Jun ; LU Xiao2Hua ; MA Jing Acta Chimica Sinica (14) 1287 In aqueous alkali metal ion solution most ions exist in a hydrated form at ambient temperature and most ions form ion pairs at elevated temperature The equilibrium constants of association reaction in MgCl 2 and CaCl 2 solutions have shown the same increase in the tendency for association as the temperature increases But there is an area where 0 1 < K < 10 In this area ion pairs and hydrated ions coexist and both hydration and association have important influences on the solution Under these conditions the two solutions can not be treated as alkali metal ion solutions and new thermodynamic model different from the one for NaCl solution must be established for them Laser Flash Photolysis Studies on Quinoxalines and Electron2poor Alkenes PAN Yang ; SHENG Zhen2Yu ; LI Jiang ; DAI Jing2Hua ; CHU Gao2Sheng ; YU Shu2Qin Acta Chimica Sinica (14) 1293 The photochemistry of quinoxalines 1 and 2 in acetonitrile has been investigated by using time2resolved laser flash photolytical technique The transient absorption spectra of the excited quinoxalines have been obtained The self2quenching rate constants ( k sq ) of excited triplet states of quinoxalines and the rate constants ( k q ) for the reactions between excited triplet states of 1 2 and five electron2poor alkenes have been determined respectively by using 266 nm laser at room temperature In addition the mechanism of the quenching of transient species has also been suggested Study on the Redox Metabolism Mechanism of Aclacinomycin2A CHENG Gui2Fang ; DING Min ; ZHAO Jie ; HE Pin2Gang ; FANG Yu2Zhi Acta Chimica Sinica (14) 1299 This is a figure of in2situ spectra of ACM2 A in physiomedium ( ph = 713) under different potential applied ( a ) open circuit ; V applited for ( b) 110 min and (c) 60 min V applied for (d) 011 min (e) 1 min (f) 3 min and (g) 120 min The absorption peak at nm represents the 2 3 transition of anthracence ring of ACM When the potential of V applied a new absorption peak at 410 nm rose and then gradually cut down and the peak at nm rose again and gradually shift to 465 nm Combined with othe methods the absorption peak at 410 nm representing hydroaclarimycinone2a was comfirmed and it was unstable at the end it formed 72deoxyaclarimycinone and then associated