2004 62 14 1299 1304 ACTA CHIMICA SINICA Vol 62 2004 No 14 1299 1304 2A Ξ Ξ ( 200062) 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 200062) 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 : yuzhi @online sh cn Received October 27 2003 ; revised February 17 2004 ; accepted March 29 2004 (No 2985008)
1300 Vol 62 2004 1 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 1 2 1 E2ACM ACM Ag/ AgCl ( KCl) ACM ACM CV ADM DNR 4 7 10 13 7 1 2 2 Kleyer [7] ACM ACM (010-015 - 0180 V) 72 ; Baldt [8] ; ACM2A 72 ACM ACM 2 1 ACM2A - 0120-0180 V ACM2A P c1 ( E Pc1 = - 01505 V) P c2 ( E Pc2 = - 01617 V) P a ACM2A ( E Pa = - 01530 V) P c1 ( 2) P c1 P c2 P a 1 2 1 1 (0101 012 V/ s) ACM2A ( ) ph = 710 PBS (012 015 4 43415 nm ( = V/ s) ; i Pa / i Pc2 12000 L/ mol cm) ( > 1 V/ s) 1 ; Anson [10] ACM2A [9] ( 1) P c1 P c2
No 14 : 2A 1301 (ph = 310) ACM2A P c2 P a CV P c1 i Pa / i Pc 1 E p = ; i Pc1 01040 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] - 0 80 V c ACM2A = 3 6 10-5 mol/ L i Pa / i Pc2 ( 2) ACM2A 2 2 ACM2A 2 2 1 ACM2A ACM2A 7 9 10 ACM2A CD ( 3 a) 224 nm K K 2 3 ;270 nm B 2 3 ;328 nm R n2 3 ; 396 nm 464 nm 4 6 10 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 - 0 20 to ACM2A Scan rate/ (V s - 1 ) 1 ACM2A Table 1 The cyclic voltammogram parameters of ACM2A (ph = 7 0) Cathodic wave i Pc1 10 6 / A E Pc1 / V i Pc2 10 6 / A E Pc2 / V Anodic wave i Pa 10 6 / A E Pa / V 0 01 0 743-0 476 3 556-0 598 0 825-0 497 0 02 1 201-0 480 6 625-0 609 1 721-0 517 0 05 2 180-0 489 11 61-0 616 3 544-0 535 0 10 3 139-0 505 19 53-0 617 6 840-0 530 0 20 7 821-0 512 35 19-0 621 15 43-0 507 0 50 15 92-0 517 65 71-0 624 38 36-0 480 2 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 0 01-0 449 0 308-0 374 0 178-0 673 0 1641-0 629 0 050 0 02-0 443 0 436-0 372 0 286-0 663 0 2451-0 628 0 072 0 05-0 456 0 996-0 419 0 718-0 648 0 3519-0 628 0 102 0 10-0 462 1 432-0 422 1 390-0 666 0 7818-0 632 0 245 0 20-0 466 2 767-0 387 2 650-0 670 1 272-0 586 0 521 0 50-0 473 6 029-0 352 6 316-0 665 2 471-0 581 1 034
1302 Vol 62 2004 3 ACM2A Figure 3 Circular dichroism spectra of ACM2A in physio2medium ph = 7 3 (a) open circular (b) - 0 500 V applied for 25 min - 0 800 V applied for (c) 0 1 min (d) 3 min (e) 59 min c ACM2A = 5 64 10-5 mol/ L 2 2 2 - ACM2A - ACM2A ACM2A 4 228 258 285 43415 nm ( 4 a) - 0150 V ( ) ACM2A mol/ L) CV ( 4 b c) - 0180 V 410 43415 nm ( 4 d e) 410 nm 2A ACM2A ( 4 f) 43415 nm 465 nm( 4 g) - 01540 410 nm 43415 nm - 01640 V ACM2A ACM2A n = 1194 P c2 ACM2A ( E o ) - 01581 V (vs1 Ag/ AgCl) 410 nm 2A ph = 310 410 nm 43415 nm ; ph = 910 410 nm 43415 nm 470 nm ACM2A 2A [12] Zn 2 + Zn 2 + 2 ( c + Zn = 510 10-4 mol/ L c ACM2A = 710 ; ACM2A 43415 nm 2A 2A = 019932 3115 mv 72 10-5 i Pa ACM2A 434 nm ; 7 72 2(72 ) 72 4 5 6 43415 nm 465 nm 3 4 ACM2A - Figure 4 UV2visible spectra of ACM2A in physiomedium ph = 7 3 c ACM2A = 6 75 10-5 mol/ L (a) open circuit - 0 500 V applied for (b) 1 0 min and (c) 60 min - 0 800 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
No 14 : 2A 1303 5 ACM2A Figure 5 The metabolism scheme of ACM2A ACM DNR [9] ADM [13] ACM 3 Nabiev I ; Chourpa I ; Manfait M J Phys Chem 1994 98 ACM 4 Tanaka A ; Morita J ; DNR ADM 1982 46 Komano T Agric Biol Chem ACM ADM DNR 5 Utsuno K ; Tsuboi M Chem Pharm Bull 1997 45 DNA 6 Junping W J Pharmaceutics 2003 251 ; DNA DNA 7 Kleyer D L ; Gaudiano G ; Koch H J Am Chem Soc 1984 106 DNA 8 Boldt M ; Gaudiano G ; Koch T H J Org DNA Chem 1987 52 9 Qu H2Y ; Cheng G2F ; Peng H2Q ; He P2G ; Fang Y 2Z Chem J Chin Univ 2002 22 2000 (in Chinese) ( 2002 22 2000 ) 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 1996 60 2 Laine A ; Halo L ; Rgty K ; Kunnai T ; Mgntsglg P ; Ylihonko K Eur J Cancer 2002 38 (Suppl ) S117 Electroanalytical Chemistry Beijing Universiey Publisher Beijing 1983 pp 16 24 (in Chinese) (Anson F 1983 pp 16 24 ) 11 Anson F ; Huang H2Z ; Gao X2X Electrochemistry and Electroanalytical Chemistry Beijing Universiey Publisher Beijing 1983 pp 52 24 (in Chinese)
1304 Vol 62 2004 (Anson F ; 13 Fen M ; Yang Y2L ; He P2G ; Fang Y2Z Chem J 1983 pp 52 54 ) 12 Fang Y2Z ; Jiang J 2C Chin J Anal Chem 1996 24 1371 (in Chinese) ( 1996 24 1371 ) Chin Univ 1999 20 (6) 866 (in Chinese) ( 1999 20 (6) 866 ) (A0310277 LU Y J ; DONG H Z )
Graphical Abstract Vol 62 2004 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 2004 62 (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 2004 62 (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 2004 62 (14) 1299 This is a figure of in2situ spectra of ACM2 A in physiomedium ( ph = 713) under different potential applied ( a ) open circuit ; - 01500 V applited for ( b) 110 min and (c) 60 min - 01800 V applied for (d) 011 min (e) 1 min (f) 3 min and (g) 120 min The absorption peak at 43515 nm represents the 2 3 transition of anthracence ring of ACM When the potential of - 0180 V applied a new absorption peak at 410 nm rose and then gradually cut down and the peak at 43515 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