Adozelesin
Adozelesin, also known as U 73975 or adolezesin, is an experimental antitumor drug of the duocarmycin class. Adozelesin is the first of a class of DNA-sequence-selective alkylating agents, the cyclopropa(c)pyrrolo(3,2-e)indol-4(5H)-ones (CPls), that have been shown to have of potent inhibitory properties of DNA synthesis. It binds to and alkylates DNA, resulting in a reduction of both cellular and simian virus 40 (SV40) DNA replication which ultimately reduces the rate of cancer growth. Phase I and Phase II clinical trials were conducted in 2000s, however, it was found adozelesin had marginal efficacy in the treatment of metastatic breast cancer at the dosage and schedule used.
1: Hopton SR, Thompson AS. Manipulative interplay of two adozelesin molecules with d(ATTAAT)₂achieving ligand-stacked Watson-Crick and Hoogsteen base-paired duplex adducts. Biochemistry. 2011 May 17;50(19):4143-54. doi: 10.1021/bi101945a. Epub 2011 Apr 19. PubMed PMID: 21469674.
2: Lee SY, Pfeifer GP, Lee CS. Mutation spectra induced by adozelesin in the supF gene of human XP-A fibroblasts. Arch Pharm Res. 2010 Apr;33(4):633-6. doi: 10.1007/s12272-010-0419-7. Epub 2010 Apr 27. PubMed PMID: 20422374.
3: Yanow SK, Purcell LA, Spithill TW. The A/T-specific DNA alkylating agent adozelesin inhibits Plasmodium falciparum growth in vitro and protects mice against Plasmodium chabaudi adami infection. Mol Biochem Parasitol. 2006 Jul;148(1):52-9. Epub 2006 Mar 23. PubMed PMID: 16597469.
4: Cao PR, McHugh MM, Melendy T, Beerman T. The DNA minor groove-alkylating cyclopropylpyrroloindole drugs adozelesin and bizelesin induce different DNA damage response pathways in human colon carcinoma HCT116 cells. Mol Cancer Ther. 2003 Jul;2(7):651-9. PubMed PMID: 12883038.
5: Liu JS, Kuo SR, Beerman TA, Melendy T. Induction of DNA damage responses by adozelesin is S phase-specific and dependent on active replication forks. Mol Cancer Ther. 2003 Jan;2(1):41-7. PubMed PMID: 12533671.
6: Wang Y, Beerman TA, Kowalski D. Antitumor drug adozelesin differentially affects active and silent origins of DNA replication in yeast checkpoint kinase mutants. Cancer Res. 2001 May 1;61(9):3787-94. PubMed PMID: 11325853.
7: Jin SG, Choi JH, Ahn B, O'Connor TR, Mar W, Lee CS. Excision repair of adozelesin-N3 adenine adduct by 3-methyladenine-DNA glycosylases and UvrABC nuclease. Mol Cells. 2001 Feb 28;11(1):41-7. PubMed PMID: 11266119.
8: Cameron L, Thompson AS. Determination of the structural role of the linking moieties in the DNA binding of adozelesin. Biochemistry. 2000 May 2;39(17):5004-12. PubMed PMID: 10819964.
9: Liu JS, Kuo SR, McHugh MM, Beerman TA, Melendy T. Adozelesin triggers DNA damage response pathways and arrests SV40 DNA replication through replication protein A inactivation. J Biol Chem. 2000 Jan 14;275(2):1391-7. PubMed PMID: 10625690.
10: Weinberger M, Trabold PA, Lu M, Sharma K, Huberman JA, Burhans WC. Induction by adozelesin and hydroxyurea of origin recognition complex-dependent DNA damage and DNA replication checkpoints in Saccharomyces cerevisiae. J Biol Chem. 1999 Dec 10;274(50):35975-84. PubMed PMID: 10585487.
11: Hidalgo M, Izbicka E, Cerna C, Gomez L, Rowinsky EK, Weitman SD, Von Hoff DD. Comparative activity of the cyclopropylpyrroloindole compounds adozelesin, bizelesin and carzelesin in a human tumor colony-forming assay. Anticancer Drugs. 1999 Mar;10(3):295-302. PubMed PMID: 10327036.
12: Yoon JH, Lee CS. Sequence selectivity of DNA alkylation by adozelesin and carzelesin. Arch Pharm Res. 1998 Aug;21(4):385-90. PubMed PMID: 9875464.
13: Cristofanilli M, Bryan WJ, Miller LL, Chang AY, Gradishar WJ, Kufe DW, Hortobagyi GN. Phase II study of adozelesin in untreated metastatic breast cancer. Anticancer Drugs. 1998 Oct;9(9):779-82. PubMed PMID: 9840723.
14: Baraldi PG, Cacciari B, Romagnoli R, Spalluto G, Gambari R, Bianchi N, Passadore M, Ambrosino P, Mongelli N, Cozzi P, Geroni C. Synthesis, cytotoxicity, antitumor activity and sequence selective binding of two pyrazole analogs structurally related to the antitumor agents U-71,184 and adozelesin. Anticancer Drug Des. 1997 Oct;12(7):555-76. PubMed PMID: 9365502.
15: Burris HA, Dieras VC, Tunca M, Earhart RH, Eckardt JR, Rodriguez GI, Shaffer DS, Fields SM, Campbell E, Schaaf L, Kasunic D, Von Hoff DD. Phase I study with the DNA sequence-specific agent adozelesin. Anticancer Drugs. 1997 Jul;8(6):588-96. PubMed PMID: 9300573.
16: Cobuzzi RJ Jr, Burhans WC, Beerman TA. Inhibition of initiation of simian virus 40 DNA replication in infected BSC-1 cells by the DNA alkylating drug adozelesin. J Biol Chem. 1996 Aug 16;271(33):19852-9. PubMed PMID: 8702695.
17: Foster BJ, LoRusso PM, Poplin E, Zalupski M, Valdivieso M, Wozniak A, Flaherty L, Kasunic DA, Earhart RH, Baker LH. Phase I trial of Adozelesin using the treatment schedule of daily x5 every 3 weeks. Invest New Drugs. 1996;13(4):321-6. PubMed PMID: 8824350.
18: Smith KS, Folz BA, Adams EG, Bhuyan BK. Synergistic and additive combinations of several antitumor drugs and other agents with the potent alkylating agent adozelesin. Cancer Chemother Pharmacol. 1995;35(6):471-82. PubMed PMID: 7533669.
19: Lee CS, Pfeifer GP, Gibson NW. Mapping of DNA alkylation sites induced by adozelesin and bizelesin in human cells by ligation-mediated polymerase chain reaction. Biochemistry. 1994 May 17;33(19):6024-30. PubMed PMID: 8180230.
20: Fleming GF, Ratain MJ, O'Brien SM, Schilsky RL, Hoffman PC, Richards JM, Vogelzang NJ, Kasunic DA, Earhart RH. Phase I study of adozelesin administered by 24-hour continuous intravenous infusion. J Natl Cancer Inst. 1994 Mar 2;86(5):368-72. PubMed PMID: 8308929.
2: Lee SY, Pfeifer GP, Lee CS. Mutation spectra induced by adozelesin in the supF gene of human XP-A fibroblasts. Arch Pharm Res. 2010 Apr;33(4):633-6. doi: 10.1007/s12272-010-0419-7. Epub 2010 Apr 27. PubMed PMID: 20422374.
3: Yanow SK, Purcell LA, Spithill TW. The A/T-specific DNA alkylating agent adozelesin inhibits Plasmodium falciparum growth in vitro and protects mice against Plasmodium chabaudi adami infection. Mol Biochem Parasitol. 2006 Jul;148(1):52-9. Epub 2006 Mar 23. PubMed PMID: 16597469.
4: Cao PR, McHugh MM, Melendy T, Beerman T. The DNA minor groove-alkylating cyclopropylpyrroloindole drugs adozelesin and bizelesin induce different DNA damage response pathways in human colon carcinoma HCT116 cells. Mol Cancer Ther. 2003 Jul;2(7):651-9. PubMed PMID: 12883038.
5: Liu JS, Kuo SR, Beerman TA, Melendy T. Induction of DNA damage responses by adozelesin is S phase-specific and dependent on active replication forks. Mol Cancer Ther. 2003 Jan;2(1):41-7. PubMed PMID: 12533671.
6: Wang Y, Beerman TA, Kowalski D. Antitumor drug adozelesin differentially affects active and silent origins of DNA replication in yeast checkpoint kinase mutants. Cancer Res. 2001 May 1;61(9):3787-94. PubMed PMID: 11325853.
7: Jin SG, Choi JH, Ahn B, O'Connor TR, Mar W, Lee CS. Excision repair of adozelesin-N3 adenine adduct by 3-methyladenine-DNA glycosylases and UvrABC nuclease. Mol Cells. 2001 Feb 28;11(1):41-7. PubMed PMID: 11266119.
8: Cameron L, Thompson AS. Determination of the structural role of the linking moieties in the DNA binding of adozelesin. Biochemistry. 2000 May 2;39(17):5004-12. PubMed PMID: 10819964.
9: Liu JS, Kuo SR, McHugh MM, Beerman TA, Melendy T. Adozelesin triggers DNA damage response pathways and arrests SV40 DNA replication through replication protein A inactivation. J Biol Chem. 2000 Jan 14;275(2):1391-7. PubMed PMID: 10625690.
10: Weinberger M, Trabold PA, Lu M, Sharma K, Huberman JA, Burhans WC. Induction by adozelesin and hydroxyurea of origin recognition complex-dependent DNA damage and DNA replication checkpoints in Saccharomyces cerevisiae. J Biol Chem. 1999 Dec 10;274(50):35975-84. PubMed PMID: 10585487.
11: Hidalgo M, Izbicka E, Cerna C, Gomez L, Rowinsky EK, Weitman SD, Von Hoff DD. Comparative activity of the cyclopropylpyrroloindole compounds adozelesin, bizelesin and carzelesin in a human tumor colony-forming assay. Anticancer Drugs. 1999 Mar;10(3):295-302. PubMed PMID: 10327036.
12: Yoon JH, Lee CS. Sequence selectivity of DNA alkylation by adozelesin and carzelesin. Arch Pharm Res. 1998 Aug;21(4):385-90. PubMed PMID: 9875464.
13: Cristofanilli M, Bryan WJ, Miller LL, Chang AY, Gradishar WJ, Kufe DW, Hortobagyi GN. Phase II study of adozelesin in untreated metastatic breast cancer. Anticancer Drugs. 1998 Oct;9(9):779-82. PubMed PMID: 9840723.
14: Baraldi PG, Cacciari B, Romagnoli R, Spalluto G, Gambari R, Bianchi N, Passadore M, Ambrosino P, Mongelli N, Cozzi P, Geroni C. Synthesis, cytotoxicity, antitumor activity and sequence selective binding of two pyrazole analogs structurally related to the antitumor agents U-71,184 and adozelesin. Anticancer Drug Des. 1997 Oct;12(7):555-76. PubMed PMID: 9365502.
15: Burris HA, Dieras VC, Tunca M, Earhart RH, Eckardt JR, Rodriguez GI, Shaffer DS, Fields SM, Campbell E, Schaaf L, Kasunic D, Von Hoff DD. Phase I study with the DNA sequence-specific agent adozelesin. Anticancer Drugs. 1997 Jul;8(6):588-96. PubMed PMID: 9300573.
16: Cobuzzi RJ Jr, Burhans WC, Beerman TA. Inhibition of initiation of simian virus 40 DNA replication in infected BSC-1 cells by the DNA alkylating drug adozelesin. J Biol Chem. 1996 Aug 16;271(33):19852-9. PubMed PMID: 8702695.
17: Foster BJ, LoRusso PM, Poplin E, Zalupski M, Valdivieso M, Wozniak A, Flaherty L, Kasunic DA, Earhart RH, Baker LH. Phase I trial of Adozelesin using the treatment schedule of daily x5 every 3 weeks. Invest New Drugs. 1996;13(4):321-6. PubMed PMID: 8824350.
18: Smith KS, Folz BA, Adams EG, Bhuyan BK. Synergistic and additive combinations of several antitumor drugs and other agents with the potent alkylating agent adozelesin. Cancer Chemother Pharmacol. 1995;35(6):471-82. PubMed PMID: 7533669.
19: Lee CS, Pfeifer GP, Gibson NW. Mapping of DNA alkylation sites induced by adozelesin and bizelesin in human cells by ligation-mediated polymerase chain reaction. Biochemistry. 1994 May 17;33(19):6024-30. PubMed PMID: 8180230.
20: Fleming GF, Ratain MJ, O'Brien SM, Schilsky RL, Hoffman PC, Richards JM, Vogelzang NJ, Kasunic DA, Earhart RH. Phase I study of adozelesin administered by 24-hour continuous intravenous infusion. J Natl Cancer Inst. 1994 Mar 2;86(5):368-72. PubMed PMID: 8308929.
| Chemical | |
|---|---|
| CAS Num | 110314-48-2 |
| Chemical Formula | C30H22N4O4 |
| Molecular Weight | 502.53 |
| IUPAC Chemical Name | N-(2-((7bR,8aS)-7-methyl-4-oxo-1,2,4,5,8,8a-hexahydrocyclopropa[c]pyrrolo[3,2-e]indole-2-carbonyl)-1H-indol-5-yl)benzofuran-2-carboxamide |
| Exact Mass | 502.16411 |
| Elemental Analysis | C, 71.70; H, 4.41; N, 11.15; O, 12.73 |
| Synonym | U73975; U-73975; U 73975; adozelesin; adolezesin. |
| Solubility | Soluble in DMSO, not in water |
| SMILES Code | O=C(C1=CC2=CC=CC=C2O1)NC3=CC4=C(NC(C(N5C[C@](C6)([H])[C@]76C8=C(NC=C8C)C(C=C57)=O)=O)=C4)C=C3 |
| Biological | |
| Targets and Effects | NA |
| Pathways | alkylating agent |
| Physical | |
| Appearance | Solid powder |
| Purity | >98% (or refer to the Certificate of Analysis) |
| Shipping Condition | Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs. |
| Storage Condition | Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). |
| Shelf Life | >2 years if stored properly |
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