337:
236:
395:
322:
446:
227:
hydroxyl radicals, which in turn react with DNA. The location and binding of Iron (II) to DNA may play an important role in determining the substrate and nature of the radical attack on the DNA. The Fenton reaction generates two types of oxidants, Type I and Type II. Type I oxidants are moderately sensitive to peroxides and ethanol. Type I and Type II oxidants preferentially cleave at the specific sequences.
428:
370:
280:
271:. Upon addition of the hydroxyl radical, many stable products can be formed. In general, radical hydroxyl attacks on base moieties do not cause altered sugars or strand breaks except when the modifications labilize the N-glycosyl bond, allowing the formation of baseless sites that are subject to beta-elimination.
327:
In the presence of DNA, the 1,4-didehydrobenzene diradical abstracts hydrogens from the deoxyribose sugar backbone, predominantly at the C-1’, C-4’ and C-5’ positions. Hydrogen abstraction causes radical formation at the reacted carbon. The carbon radical reacts with molecular oxygen, which leads to
364:
was one of the first such products identified and was originally found in a soil sample taken from
Kerrville, Texas. These compounds are synthesized by bacteria as defense mechanisms due to their ability to cleave DNA through the formation of 1,4-didehydrobenzene from the enediyne component of the
259:
is the repair mechanism used. Hydroxyl radical reactions with the deoxyribose sugar backbone are initiated by hydrogen abstraction from a deoxyribose carbon, and the predominant consequence is eventual strand breakage and base release. The hydroxyl radical reacts with the various hydrogen atoms of
197:
with a free coordination site are capable of reducing peroxides to hydroxyl radicals. Iron is believed to be the metal responsible for the creation of hydroxyl radicals because it exists at the highest concentration of any transition metal in most living organisms. The Fenton reaction is possible
375:
Calicheamicin and other related compounds share several common characteristics. The extended structures attached to the enediyne allow the compound to specifically bind DNA, in most cases to the minor groove of the double helix. Additionally, part of the molecule is known as the “trigger” which,
287:
Hydrogen abstraction from the 1’-deoxyribose carbon by the hydroxyl radical creates a 1 ‘-deoxyribosyl radical. The radical can then react with molecular oxygen, creating a peroxyl radical which can be reduced and dehydrated to yield a 2’-deoxyribonolactone and free base. A deoxyribonolactone is
296:
Radical damage to DNA can also occur through the interaction of DNA with certain natural products known as radiomimetic compounds, molecular compounds which affect DNA in similar ways to radiation exposure. Radiomimetic compounds induce double-strand breaks in DNA via highly specific, concerted
459:
Most enediynes, including the ones listed above, have been used as potent antitumor antibiotics due to their ability to efficiently cleave DNA. Calicheamicin and esperamicin are the two most commonly used types due to their high specificity when binding to DNA, which minimizes unfavorable side
226:
The creation of hydroxyl radicals by iron(II) catalysis is important because iron(II) can be found coordinated with, and therefore in close proximity to, DNA. This reaction allows for hydrogen peroxide created by radiolysis of water to diffuse to the nucleus and react with Iron (II) to produce
478:
generates a free radical under anoxic conditions instead of the trigger mechanism of an enediyne. The free radical then continues on to cleave DNA in a similar manner to 1,4-didehydrobenzene in order to treat cancerous cells. It is currently in Phase III trials.
328:
a strand break in the DNA through a variety of mechanisms. 1,4-Didehydrobenzene is able to position itself in such a way that it can abstract proximal hydrogens from both strands of DNA. This produces a double-strand break in the DNA, which can lead to cellular
98:
damage is caused by hydroxyl radicals, yet hydroxyl radicals are so reactive that they can only diffuse one or two molecular diameters before reacting with cellular components. Thus, hydroxyl radicals must be formed immediately adjacent to
342:
Enediynes generally undergo the
Bergman cyclization at temperatures exceeding 200 °C. However, incorporating the enediyne into a 10-membered cyclic hydrocarbon makes the reaction more thermodynamically favorable by releasing the
347:
of the reactants. This allows for the
Bergman cyclization to occur at 37 °C, the biological temperature of humans. Molecules which incorporate enediynes into these larger ring structures have been found to be extremely
103:
in order to react. Radiolysis of water creates peroxides that can act as diffusable, latent forms of hydroxyl radicals. Some metal ions in the vicinity of DNA generate the hydroxyl radicals from peroxide.
360:
Enediynes are present in many complicated natural products. They were originally discovered in the early 1980s during a search for new anticancer products produced by microorganisms.
198:
because transition metals can exist in more than one oxidation state and their valence electrons may be unpaired, allowing them to participate in one-electron redox reactions.
789:
Steenken S (1989). "Purine bases, nuclesides and nucleotides: aqueous solution redox chemistry and transformation reactions of their radical cations and e- and OH adducts".
63:
can be caused by indirect DNA damage because it is found in parts of the body not exposed to sunlight. DNA is vulnerable to radical attack because of the very
260:
the deoxyribose in the order 5′ H > 4′ H > 3′ H ≈ 2′ H ≈ 1′ H. This order of reactivity parallels the exposure to solvent of the deoxyribose hydrogens.
1100:
Zein N, Sinha AM, McGahren WJ, Ellestad GA (May 1988). "Calicheamicin gamma 1I: an antitumor antibiotic that cleaves double-stranded DNA site specifically".
695:
Pogozelski WK, Tullius TD (May 1998). "Oxidative Strand
Scission of Nucleic Acids: Routes Initiated by Hydrogen Abstraction from the Sugar Moiety".
451:
The chromophore is unreactive when bound to the apoprotein. Upon its release, it reacts to form 1,4-didehydrobenzene and subsequently cleaves DNA.
1063:"Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate"
1062:
394:
566:
263:
Hydroxyl radicals react with DNA bases via addition to the electron-rich, pi bonds. These pi bonds in the bases are located between C5-C6 of
390:
The calicheamicin types are defined by a methyl trisulfide group that is involved in triggering the molecule by the following mechanism.
321:
445:
851:
Povirk LF (1996). "DNA damage and mutagenesis by radiomimetic DNA-cleaving agents: Bleomycin, neocarzinostatin and other enediynes".
617:
732:"DNA strand breaking by the hydroxyl radical is governed by the accessible surface areas of the hydrogen atoms of the DNA backbone"
964:
Ellestad GA (September 2011). "Structural and conformational features relevant to the anti-tumor activity of calicheamicin γ 1I".
499:
31:
1061:
Sievers EL, Appelbaum FR, Spielberger RT, Forman SJ, Flowers D, Smith FO, Shannon-Dorcy K, Berger MS, Bernstein ID (June 1999).
317:
diradical. The 1,4-didehydrobenzene diradical is highly reactive, and will abstract hydrogens from any possible hydrogen-donor.
189:
results in the creation of hydroxyl radicals from hydrogen peroxide and an Iron (II) catalyst. Iron(III) is regenerated via the
376:
under specific physiological conditions, activates the enediyne, known as the “warhead” and 1,4-didehydrobenzene is generated.
255:. Cells have developed complex and efficient repair mechanisms to fix the lesions. In the case of free radical attack on DNA,
467:
Additionally, calicheamicin is able to cleave DNA at low concentrations, proving to be up to 1000 times more effective than
336:
235:
411:
and enediyne core. The anthraquinone component allows for specific binding of DNA at the 3’ side of purine bases through
829:
412:
1257:
1004:"DNA intercalation and cleavage of an antitumor antibiotic dynemicin that contains anthracycline and enediyne cores"
602:
DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability
415:, a site that is different from calicheamicin. Its ability to cleave DNA is greatly increased in the presence of
64:
502:
caused by oxidative free radicals has been hypothesized to be a major driving force in the evolution of meiosis
190:
461:
72:
243:
Hydroxyl radicals can attack the deoxyribose DNA backbone and bases, potentially causing a plethora of
1109:
1015:
743:
256:
1252:
491:
310:
56:
816:
Lhomme J, Constant JF, Demeunynck M (1999). "Abasic DNA structure, reactivity, and recognition".
672:
60:
44:
1223:
1174:
1125:
1082:
1043:
981:
943:
868:
833:
771:
712:
664:
623:
613:
582:
562:
194:
1213:
1205:
1164:
1156:
1117:
1074:
1033:
1023:
973:
933:
902:
860:
825:
798:
761:
751:
704:
654:
605:
572:
554:
91:
604:. Progress in Nucleic Acid Research and Molecular Biology. Vol. 35. pp. 95–125.
186:
893:
Kraka E, Cremer D (2000). "Computer design of anticancer drugs. A new enediyne warhead".
1113:
1019:
747:
177:
Free radical damage to DNA is thought to cause mutations that may lead to some cancers.
1218:
1193:
1169:
1144:
577:
542:
474:
The free radical mechanism to treat certain types of cancers extends beyond enediynes.
438:
609:
1241:
1038:
1003:
864:
766:
731:
408:
384:
361:
59:
because the radicals formed can diffuse throughout the body and affect other organs.
27:
Damage to DNA as a result of exposure to ionizing radiation or radiomimetic compounds
676:
1247:
475:
100:
52:
17:
938:
921:
558:
522:
Barbusinski K (2009). "Fenton
Reaction – Controversy Concerning the Chemistry".
434:
401:
380:
344:
1008:
Proceedings of the
National Academy of Sciences of the United States of America
736:
Proceedings of the
National Academy of Sciences of the United States of America
404:
have been used as anticancer drugs due to their high toxicity and specificity.
1160:
1078:
495:
468:
264:
83:
35:
659:
642:
1121:
1028:
922:"A new macromolecular antitumor antibiotic, C-1027. III. Antitumor activity"
756:
349:
329:
288:
mutagenic and resistant to repair enzymes. Thus, an abasic site is created.
252:
248:
68:
1227:
1209:
1178:
1086:
985:
837:
716:
643:"Formation, prevention, and repair of DNA damage by iron/hydrogen peroxide"
586:
369:
1129:
1047:
947:
872:
775:
668:
627:
423:
compounds. This compound has also found prominence as an antitumor agent.
306:
297:
free-radical attacks on the deoxyribose moieties in both strands of DNA.
87:
802:
427:
977:
487:
906:
708:
379:
Three classes of enediynes have since been identified: calicheamicin,
853:
Mutation
Research/Fundamental and Molecular Mechanisms of Mutagenesis
460:
reactions. They have been shown to be especially useful for treating
268:
244:
407:
Dynemicin and its relatives are characterized by the presence of an
279:
920:
Zhen YS, Ming XY, Yu B, Otani T, Saito H, Yamada Y (August 1989).
420:
416:
314:
278:
234:
67:
that can be abstracted and the prevalence of double bonds in the
830:
10.1002/1097-0282(1999)52:2<65::aid-bip1>3.3.co;2-l
95:
48:
730:
Balasubramanian B, Pogozelski WK, Tullius TD (August 1998).
433:
Chromoprotein enediynes are characterized by an unstable
1145:"The oxidative damage initiation hypothesis for meiosis"
86:
of intracellular water by ionizing radiation creates
1002:Sugiura Y, Shiraki T, Konishi M, Oki T (May 1990).
239:Radical hydroxyl attacks can form baseless sites
517:
515:
292:Radical damage through radiomimetic compounds
8:
90:, which are relatively stable precursors to
959:
957:
997:
995:
1217:
1168:
1037:
1027:
937:
765:
755:
658:
576:
1194:"How oxygen gave rise to eukaryotic sex"
888:
886:
884:
882:
47:or to radiomimetic compounds. Damage to
511:
471:at combating certain types of tumors.
1192:Hörandl E, Speijer D (February 2018).
1143:Hörandl E, Hadacek F (December 2013).
690:
688:
686:
547:Advances in Physical Organic Chemistry
400:Calicheamicin and the closely related
543:"Reactivity of Nucleic Acid Radicals"
283:Route of deoxyribonolactone formation
43:can occur as a result of exposure to
7:
524:Ecological Chemistry and Engineering
647:The Journal of Biological Chemistry
25:
641:Henle ES, Linn S (August 1997).
444:
426:
393:
368:
335:
320:
305:Many radiomimetic compounds are
32:DNA damage (naturally occurring)
1:
610:10.1016/s0079-6603(08)60611-x
79:Damage via radiation exposure
865:10.1016/0027-5107(96)00023-1
73:free radicals can easily add
939:10.7164/antibiotics.42.1294
559:10.1016/bs.apoc.2016.02.001
1274:
926:The Journal of Antibiotics
41:Free radical damage to DNA
29:
1161:10.1007/s00497-013-0234-7
1079:10.1182/blood.V93.11.3678
660:10.1074/jbc.272.31.19095
490:is a central feature of
1122:10.1126/science.3240341
1029:10.1073/pnas.87.10.3831
757:10.1073/pnas.95.17.9738
231:Radical hydroxyl attack
1210:10.1098/rspb.2017.2706
462:acute myeloid leukemia
313:reaction to produce a
284:
240:
94:. 60%–70% of cellular
553:. Elsevier: 119–202.
541:Greenberg MM (2016).
498:. The need to repair
437:enediyne bound to an
282:
238:
500:oxidative DNA damage
483:Evolution of Meiosis
315:1,4-didehydrobenzene
309:, which undergo the
257:base-excision repair
191:Haber–Weiss reaction
1114:1988Sci...240.1198Z
1020:1990PNAS...87.3831S
803:10.1021/cr00093a003
748:1998PNAS...95.9738B
492:sexual reproduction
311:Bergman cyclization
181:The Fenton reaction
57:indirect DNA damage
18:Free radical damage
1258:Molecular genetics
1108:(4856): 1198–201.
978:10.1002/chir.20990
285:
241:
61:Malignant melanoma
45:ionizing radiation
907:10.1021/ja001017k
901:(34): 8245–8264.
709:10.1021/cr960437i
568:978-0-12-804716-3
455:Antitumor ability
387:-based products.
332:if not repaired.
301:General mechanism
195:Transition metals
92:hydroxyl radicals
55:attack is called
16:(Redirected from
1265:
1232:
1231:
1221:
1189:
1183:
1182:
1172:
1140:
1134:
1133:
1097:
1091:
1090:
1058:
1052:
1051:
1041:
1031:
999:
990:
989:
961:
952:
951:
941:
917:
911:
910:
895:J. Am. Chem. Soc
890:
877:
876:
848:
842:
841:
813:
807:
806:
786:
780:
779:
769:
759:
727:
721:
720:
703:(3): 1089–1108.
697:Chemical Reviews
692:
681:
680:
662:
638:
632:
631:
600:Ward JF (1988).
597:
591:
590:
580:
538:
532:
531:
519:
448:
430:
397:
372:
356:Natural products
339:
324:
65:labile hydrogens
21:
1273:
1272:
1268:
1267:
1266:
1264:
1263:
1262:
1238:
1237:
1236:
1235:
1191:
1190:
1186:
1142:
1141:
1137:
1099:
1098:
1094:
1073:(11): 3678–84.
1060:
1059:
1055:
1001:
1000:
993:
963:
962:
955:
919:
918:
914:
892:
891:
880:
850:
849:
845:
815:
814:
810:
788:
787:
783:
742:(17): 9738–43.
729:
728:
724:
694:
693:
684:
653:(31): 19095–8.
640:
639:
635:
620:
599:
598:
594:
569:
540:
539:
535:
521:
520:
513:
508:
485:
457:
358:
303:
294:
277:
233:
213:
209:
187:Fenton reaction
183:
169:
165:
151:
141:
134:
130:
123:
115:
81:
51:as a result of
38:
28:
23:
22:
15:
12:
11:
5:
1271:
1269:
1261:
1260:
1255:
1250:
1240:
1239:
1234:
1233:
1184:
1135:
1092:
1053:
1014:(10): 3831–5.
991:
953:
912:
878:
859:(1–2): 71–89.
843:
808:
797:(3): 503–529.
781:
722:
682:
633:
618:
592:
567:
533:
510:
509:
507:
504:
484:
481:
456:
453:
357:
354:
302:
299:
293:
290:
276:
273:
232:
229:
224:
223:
222:
221:
220:
219:
211:
207:
182:
179:
175:
174:
173:
172:
171:
170:
167:
163:
156:
149:
146:
139:
136:
132:
128:
125:
121:
113:
80:
77:
26:
24:
14:
13:
10:
9:
6:
4:
3:
2:
1270:
1259:
1256:
1254:
1251:
1249:
1246:
1245:
1243:
1229:
1225:
1220:
1215:
1211:
1207:
1203:
1199:
1198:Proc Biol Sci
1195:
1188:
1185:
1180:
1176:
1171:
1166:
1162:
1158:
1155:(4): 351–67.
1154:
1150:
1146:
1139:
1136:
1131:
1127:
1123:
1119:
1115:
1111:
1107:
1103:
1096:
1093:
1088:
1084:
1080:
1076:
1072:
1068:
1064:
1057:
1054:
1049:
1045:
1040:
1035:
1030:
1025:
1021:
1017:
1013:
1009:
1005:
998:
996:
992:
987:
983:
979:
975:
972:(8): 660–71.
971:
967:
960:
958:
954:
949:
945:
940:
935:
932:(8): 1294–8.
931:
927:
923:
916:
913:
908:
904:
900:
896:
889:
887:
885:
883:
879:
874:
870:
866:
862:
858:
854:
847:
844:
839:
835:
831:
827:
823:
819:
812:
809:
804:
800:
796:
792:
785:
782:
777:
773:
768:
763:
758:
753:
749:
745:
741:
737:
733:
726:
723:
718:
714:
710:
706:
702:
698:
691:
689:
687:
683:
678:
674:
670:
666:
661:
656:
652:
648:
644:
637:
634:
629:
625:
621:
619:9780125400350
615:
611:
607:
603:
596:
593:
588:
584:
579:
574:
570:
564:
560:
556:
552:
548:
544:
537:
534:
529:
525:
518:
516:
512:
505:
503:
501:
497:
493:
489:
482:
480:
477:
472:
470:
465:
463:
454:
452:
449:
447:
442:
440:
436:
431:
429:
424:
422:
418:
414:
413:intercalation
410:
409:anthraquinone
405:
403:
398:
396:
391:
388:
386:
385:chromoprotein
382:
377:
373:
371:
366:
363:
362:Calicheamicin
355:
353:
351:
346:
340:
338:
333:
331:
325:
323:
318:
316:
312:
308:
300:
298:
291:
289:
281:
274:
272:
270:
267:and N7-C8 in
266:
261:
258:
254:
250:
246:
237:
230:
228:
217:
205:
204:
203:
202:
201:
200:
199:
196:
192:
188:
180:
178:
161:
157:
155:
147:
145:
137:
126:
119:
111:
110:
109:
108:
107:
106:
105:
102:
101:nucleic acids
97:
93:
89:
85:
78:
76:
74:
70:
66:
62:
58:
54:
50:
46:
42:
37:
33:
19:
1201:
1197:
1187:
1152:
1149:Plant Reprod
1148:
1138:
1105:
1101:
1095:
1070:
1066:
1056:
1011:
1007:
969:
965:
929:
925:
915:
898:
894:
856:
852:
846:
824:(2): 65–83.
821:
817:
811:
794:
790:
784:
739:
735:
725:
700:
696:
650:
646:
636:
601:
595:
550:
546:
536:
527:
523:
486:
476:Tirapazamine
473:
466:
458:
450:
443:
432:
425:
406:
399:
392:
389:
378:
374:
367:
359:
341:
334:
326:
319:
304:
295:
286:
275:Abasic sites
262:
247:that can be
242:
225:
215:
184:
176:
159:
153:
143:
117:
82:
53:free radical
40:
39:
818:Biopolymers
435:chromophore
402:esperamicin
345:ring strain
265:pyrimidines
1253:DNA repair
1242:Categories
506:References
496:eukaryotes
469:adriamycin
439:apoprotein
365:molecule.
152:O → OH + H
142:O → H + OH
84:Radiolysis
36:DNA repair
30:See also:
966:Chirality
791:Chem. Rev
381:dynemicin
350:cytotoxic
330:apoptosis
307:enediynes
253:mutagenic
249:cytotoxic
214:→ Fe + OH
131:O + e → H
88:peroxides
69:DNA bases
1228:29436502
1204:(1872).
1179:23995700
1087:10339474
986:21800378
838:10898853
717:11848926
677:11016259
587:28529390
1219:5829205
1170:3825497
1130:3240341
1110:Bibcode
1102:Science
1048:2339123
1016:Bibcode
948:2759910
873:8781578
776:9707545
744:Bibcode
669:9235895
628:3065826
578:5435387
488:Meiosis
269:purines
245:lesions
1226:
1216:
1177:
1167:
1128:
1085:
1046:
1036:
984:
946:
871:
836:
774:
764:
715:
675:
667:
626:
616:
585:
575:
565:
383:, and
206:Fe + H
1067:Blood
1039:53997
767:21406
673:S2CID
421:thiol
417:NADPH
124:O + e
71:that
1224:PMID
1175:PMID
1126:PMID
1083:PMID
1044:PMID
982:PMID
944:PMID
869:PMID
834:PMID
772:PMID
713:PMID
665:PMID
624:PMID
614:ISBN
583:PMID
563:ISBN
530:(3).
419:and
218:+ OH
185:The
158:2 OH
116:O +
75:to.
34:and
1248:DNA
1214:PMC
1206:doi
1202:285
1165:PMC
1157:doi
1118:doi
1106:240
1075:doi
1034:PMC
1024:doi
974:doi
934:doi
903:doi
899:122
861:doi
857:355
826:doi
799:doi
762:PMC
752:doi
705:doi
655:doi
651:272
606:doi
573:PMC
555:doi
494:in
251:or
120:→ H
96:DNA
49:DNA
1244::
1222:.
1212:.
1200:.
1196:.
1173:.
1163:.
1153:26
1151:.
1147:.
1124:.
1116:.
1104:.
1081:.
1071:93
1069:.
1065:.
1042:.
1032:.
1022:.
1012:87
1010:.
1006:.
994:^
980:.
970:23
968:.
956:^
942:.
930:42
928:.
924:.
897:.
881:^
867:.
855:.
832:.
822:52
820:.
795:89
793:.
770:.
760:.
750:.
740:95
738:.
734:.
711:.
701:98
699:.
685:^
671:.
663:.
649:.
645:.
622:.
612:.
581:.
571:.
561:.
551:50
549:.
545:.
528:16
526:.
514:^
464:.
441:.
352:.
193:.
162:→H
118:hν
1230:.
1208::
1181:.
1159::
1132:.
1120::
1112::
1089:.
1077::
1050:.
1026::
1018::
988:.
976::
950:.
936::
909:.
905::
875:.
863::
840:.
828::
805:.
801::
778:.
754::
746::
719:.
707::
679:.
657::
630:.
608::
589:.
557::
216:·
212:2
210:O
208:2
168:2
166:O
164:2
160:·
154:·
150:2
148:H
144:·
140:2
138:H
135:O
133:2
129:2
127:H
122:2
114:2
112:H
20:)
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.
