Aroplatin
Aroplatin is a synthetic liposomal formulation of bis-neodecanoate diaminocyclohexane platinum (NDDP), a third-generation platinum complex analogue of cisplatin, with potential antineoplastic activity. After displacement of the 2 long-chain aliphatic leaving groups (neodecanoic acid), platinum diaminocyclohexane (DACH) complexes become highly reactive and alkylate macromolecules, forming both inter- and intra-strand DNA crosslinks and inhibiting DNA synthesis, which results in tumor cell cytotoxicity. Because DNA mismatch-repair (MMR) complexes do not recognize DACH–platinum adducts, DNA repair mechanisms are inhibited, overcoming limitations observed with other platinum-based agents. In addition, the liposomal encapsulation improves the bioavailability of NDDP and reduces its toxicity profile.
1: Kelland L. Broadening the clinical use of platinum drug-based chemotherapy with new analogues. Satraplatin and picoplatin. Expert Opin Investig Drugs. 2007 Jul;16(7):1009-21. Review. PubMed PMID: 17594186.
2: Dragovich T, Mendelson D, Kurtin S, Richardson K, Von Hoff D, Hoos A. A Phase 2 trial of the liposomal DACH platinum L-NDDP in patients with therapy-refractory advanced colorectal cancer. Cancer Chemother Pharmacol. 2006 Dec;58(6):759-64. Epub 2006 May 23. PubMed PMID: 16847673.
3: Lu C, Perez-Soler R, Piperdi B, Walsh GL, Swisher SG, Smythe WR, Shin HJ, Ro JY, Feng L, Truong M, Yalamanchili A, Lopez-Berestein G, Hong WK, Khokhar AR, Shin DM. Phase II study of a liposome-entrapped cisplatin analog (L-NDDP) administered intrapleurally and pathologic response rates in patients with malignant pleural mesothelioma. J Clin Oncol. 2005 May 20;23(15):3495-501. PubMed PMID: 15908659.
4: Verschraegen CF, Kumagai S, Davidson R, Feig B, Mansfield P, Lee SJ, Maclean DS, Hu W, Khokhar AR, Siddik ZH. Phase I clinical and pharmacological study of intraperitoneal cis-bis-neodecanoato( trans- R, R-1, 2-diaminocyclohexane)-platinum II entrapped in multilamellar liposome vesicles. J Cancer Res Clin Oncol. 2003 Oct;129(10):549-55. Epub 2003 Aug 29. PubMed PMID: 14513369.
5: MacLean DS, Khokhar AR, Perez-Soler R. Neutron activation of NDDP, a liposomal platinum antitumor agent. Cancer Biother Radiopharm. 2000 Jun;15(3):253-9. PubMed PMID: 10941532.
6: Fox LE, Rosenthal RC, King RR, Levine PB, Vail DM, Helfand SC, MacEwen EG, Perez-Soler R, Calderwood-Mays M, Kurzman ID. Use of cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II), a liposomal cisplatin analogue, in cats with oral squamous cell carcinoma. Am J Vet Res. 2000 Jul;61(7):791-5. PubMed PMID: 10895902.
7: Maclean DS, Khokhar AR, Tyle P, Perez-Soler R. Intraliposomal chemical activation patterns of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (L-NDDP)-a potential antitumour agent. J Microencapsul. 2000 May-Jun;17(3):307-22. PubMed PMID: 10819419.
8: Kelland LR. Meeting report on 8th International Symposium on Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy. J Inorg Biochem. 1999 Oct;77(1-2):121-4. PubMed PMID: 10626364.
9: Fox LE, Toshach K, Calderwood-Mays M, Khokhar AR, Kubilis P, Perez-Soler R, MacEwen EG. Evaluation of toxicosis of liposome-encapsulated cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) in clinically normal cats. Am J Vet Res. 1999 Feb;60(2):257-63. PubMed PMID: 10048562.
10: Perez-Soler R, Shin DM, Siddik ZH, Murphy WK, Huber M, Lee SJ, Khokhar AR, Hong WK. Phase I clinical and pharmacological study of liposome-entrapped NDDP administered intrapleurally in patients with malignant pleural effusions. Clin Cancer Res. 1997 Mar;3(3):373-9. PubMed PMID: 9815694.
11: Han I, Khokhar AR, Perez-Soler R. Intraliposomal conversion of lipophilic cis-bis-carboxylato-trans-R,R-1,2-diaminocyclohexane-platinum (II) complexes into cis-bis-dichloro-trans-R,R-1,2-diaminocyclohexane-platinum (II). Cancer Chemother Pharmacol. 1996;39(1-2):17-24. PubMed PMID: 8995495.
12: Mori A, Wu SP, Han I, Khokhar AR, Perez-Soler R, Huang L. In vivo antitumor activity of cis-bis-neodecanoato-trans-R,R-1, 2-diaminocyclohexane platinum(II) formulated in long-circulating liposomes. Cancer Chemother Pharmacol. 1996;37(5):435-44. PubMed PMID: 8599866.
13: Li S, Khokhar AR, Perez-Soler R, Huang L. Improved antitumor activity of cis-Bis-neodecanoato-trans-R,R-1,2- diaminocyclohexaneplatinum (II) entrapped in long-circulating liposomes. Oncol Res. 1995;7(12):611-7. PubMed PMID: 8704278.
14: Han I, Ling YH, Khokhar AR, Perez-Soler R. Cell death and DNA fragmentation induced by liposomal platinum(II) complex, L-NDDP in A2780 and A2780/PDD cells. Anticancer Res. 1994 Mar-Apr;14(2A):421-6. PubMed PMID: 8017841.
15: Han I, Nguyen T, Yang LY, Khokhar AR, Perez-Soler R. Cellular accumulation and DNA damage induced by liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum+ ++(II) in LoVo and LoVo/PDD cells. Anticancer Drugs. 1994 Feb;5(1):64-8. PubMed PMID: 8186432.
16: Perez-Soler R, Francis K, al-Baker S, Pilkiewicz F, Khokhar AR. Preparation and characterization of liposomes containing a lipophilic cisplatin derivative for clinical use. J Microencapsul. 1994 Jan-Feb;11(1):41-54. PubMed PMID: 8138874.
17: Han I, Ling YH, al-Baker S, Khokhar AR, Perez-Soler R. Cellular pharmacology of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum(II) in A2780/S and A2780/PDD cells. Cancer Res. 1993 Oct 15;53(20):4913-9. PubMed PMID: 8402681.
18: Christian MC. The current status of new platinum analogs. Semin Oncol. 1992 Dec;19(6):720-33. Review. PubMed PMID: 1462169.
19: Perez-Soler R, Khokhar AR. Lipophilic cisplatin analogues entrapped in liposomes: role of intraliposomal drug activation in biological activity. Cancer Res. 1992 Nov 15;52(22):6341-7. PubMed PMID: 1423280.
20: Khokhar AR, al-Baker S, Perez-Soler R. Toxicity and efficacy studies on a series of lipid-soluble dineodecanoato(trans-R,R- and trans-S,S-1,2-diaminocyclohexane) platinum (II) complexes entrapped in liposomes. Anticancer Drugs. 1992 Apr;3(2):95-100. PubMed PMID: 1525398.
21: Vadiei K, Siddik ZH, Khokhar AR, al-Baker S, Sampedro F, Perez-Soler R. Pharmacokinetics of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) and cisplatin given i.v. and i.p. in the rat. Cancer Chemother Pharmacol. 1992;30(5):365-9. PubMed PMID: 1505075.
22: Sugarman SM, Perez-Soler R. Liposomes in the treatment of malignancy: a clinical perspective. Crit Rev Oncol Hematol. 1992;12(3):231-42. Review. PubMed PMID: 1497823.
23: Khokhar AR, al-Baker S, Brown T, Perez-Soler R. Chemical and biological studies on a series of lipid-soluble (trans-(R,R)- and -(S,S)-1,2-diaminocyclohexane)platinum(II) complexes incorporated in liposomes. J Med Chem. 1991 Jan;34(1):325-9. PubMed PMID: 1992134.
24: Perez-Soler R, Lopez-Berestein G, Lautersztain J, al-Baker S, Francis K, Macias-Kiger D, Raber MN, Khokhar AR. Phase I clinical and pharmacological study of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II). Cancer Res. 1990 Jul 15;50(14):4254-9. PubMed PMID: 2364384.
25: Perez-Soler R, Lautersztain J, Stephens LC, Wright K, Khokhar AR. Preclinical toxicity and pharmacology of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II). Cancer Chemother Pharmacol. 1989;24(1):1-8. PubMed PMID: 2720887.
26: Khokhar AR, al-Baker S, Krakoff IH, Perez-Soler R. Toxicity and antitumor activity of cis-bis-carboxylato(trans-R,R-1,2-diaminocyclohexane) platinum(II) complexes entrapped in liposomes. Cancer Chemother Pharmacol. 1989;23(4):219-24. PubMed PMID: 2647311.
27: Khokhar AR, Al-Baker S, Perez-Soler R. Toxicity and anti-tumor activity of hydrophobic diammine and diaminocyclohexane platinum complexes entrapped in multilamellar vesicles. Anticancer Drug Des. 1988 Dec;3(3):177-84. PubMed PMID: 3207465.
28: Perez-Soler R, Yang LY, Drewinko B, Lauterzstain J, Khokhar AR. Increased cytotoxicity and reversal of resistance to cis-diamminedichloro-platinum(II) with entrapment of cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in multilamellar lipid vesicles. Cancer Res. 1988 Aug 15;48(16):4509-12. PubMed PMID: 3396003.
29: Lautersztain J, Perez-Soler R, Turpin J, Khokhar AR, Siddik ZH, Schmidt K, Lopez-Berestein G. Cellular pharmacology of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in mouse resident peritoneal macrophages, Kupffer cells, and hepatocytes. Cancer Res. 1988 Mar 1;48(5):1300-6. PubMed PMID: 3342409.
30: Khokhar AR, Wright K, Siddik ZH, Perez-Soler R. Organ distribution and tumor uptake of liposome entrapped cis-bis-neodecanoato trans-R, R-1,2 diaminocyclohexane platinum (II) administered intravenously and into the proper hepatic artery. Cancer Chemother Pharmacol. 1988;22(3):223-7. PubMed PMID: 3409456.
31: Perez-Soler R, Khokhar AR, Lopez-Berestein G. Treatment and prophylaxis of experimental liver metastases of M5076 reticulosarcoma with cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) encapsulated in multilamellar vesicles. Cancer Res. 1987 Dec 15;47(24 Pt 1):6462-6. PubMed PMID: 3315188.
2: Dragovich T, Mendelson D, Kurtin S, Richardson K, Von Hoff D, Hoos A. A Phase 2 trial of the liposomal DACH platinum L-NDDP in patients with therapy-refractory advanced colorectal cancer. Cancer Chemother Pharmacol. 2006 Dec;58(6):759-64. Epub 2006 May 23. PubMed PMID: 16847673.
3: Lu C, Perez-Soler R, Piperdi B, Walsh GL, Swisher SG, Smythe WR, Shin HJ, Ro JY, Feng L, Truong M, Yalamanchili A, Lopez-Berestein G, Hong WK, Khokhar AR, Shin DM. Phase II study of a liposome-entrapped cisplatin analog (L-NDDP) administered intrapleurally and pathologic response rates in patients with malignant pleural mesothelioma. J Clin Oncol. 2005 May 20;23(15):3495-501. PubMed PMID: 15908659.
4: Verschraegen CF, Kumagai S, Davidson R, Feig B, Mansfield P, Lee SJ, Maclean DS, Hu W, Khokhar AR, Siddik ZH. Phase I clinical and pharmacological study of intraperitoneal cis-bis-neodecanoato( trans- R, R-1, 2-diaminocyclohexane)-platinum II entrapped in multilamellar liposome vesicles. J Cancer Res Clin Oncol. 2003 Oct;129(10):549-55. Epub 2003 Aug 29. PubMed PMID: 14513369.
5: MacLean DS, Khokhar AR, Perez-Soler R. Neutron activation of NDDP, a liposomal platinum antitumor agent. Cancer Biother Radiopharm. 2000 Jun;15(3):253-9. PubMed PMID: 10941532.
6: Fox LE, Rosenthal RC, King RR, Levine PB, Vail DM, Helfand SC, MacEwen EG, Perez-Soler R, Calderwood-Mays M, Kurzman ID. Use of cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II), a liposomal cisplatin analogue, in cats with oral squamous cell carcinoma. Am J Vet Res. 2000 Jul;61(7):791-5. PubMed PMID: 10895902.
7: Maclean DS, Khokhar AR, Tyle P, Perez-Soler R. Intraliposomal chemical activation patterns of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (L-NDDP)-a potential antitumour agent. J Microencapsul. 2000 May-Jun;17(3):307-22. PubMed PMID: 10819419.
8: Kelland LR. Meeting report on 8th International Symposium on Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy. J Inorg Biochem. 1999 Oct;77(1-2):121-4. PubMed PMID: 10626364.
9: Fox LE, Toshach K, Calderwood-Mays M, Khokhar AR, Kubilis P, Perez-Soler R, MacEwen EG. Evaluation of toxicosis of liposome-encapsulated cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) in clinically normal cats. Am J Vet Res. 1999 Feb;60(2):257-63. PubMed PMID: 10048562.
10: Perez-Soler R, Shin DM, Siddik ZH, Murphy WK, Huber M, Lee SJ, Khokhar AR, Hong WK. Phase I clinical and pharmacological study of liposome-entrapped NDDP administered intrapleurally in patients with malignant pleural effusions. Clin Cancer Res. 1997 Mar;3(3):373-9. PubMed PMID: 9815694.
11: Han I, Khokhar AR, Perez-Soler R. Intraliposomal conversion of lipophilic cis-bis-carboxylato-trans-R,R-1,2-diaminocyclohexane-platinum (II) complexes into cis-bis-dichloro-trans-R,R-1,2-diaminocyclohexane-platinum (II). Cancer Chemother Pharmacol. 1996;39(1-2):17-24. PubMed PMID: 8995495.
12: Mori A, Wu SP, Han I, Khokhar AR, Perez-Soler R, Huang L. In vivo antitumor activity of cis-bis-neodecanoato-trans-R,R-1, 2-diaminocyclohexane platinum(II) formulated in long-circulating liposomes. Cancer Chemother Pharmacol. 1996;37(5):435-44. PubMed PMID: 8599866.
13: Li S, Khokhar AR, Perez-Soler R, Huang L. Improved antitumor activity of cis-Bis-neodecanoato-trans-R,R-1,2- diaminocyclohexaneplatinum (II) entrapped in long-circulating liposomes. Oncol Res. 1995;7(12):611-7. PubMed PMID: 8704278.
14: Han I, Ling YH, Khokhar AR, Perez-Soler R. Cell death and DNA fragmentation induced by liposomal platinum(II) complex, L-NDDP in A2780 and A2780/PDD cells. Anticancer Res. 1994 Mar-Apr;14(2A):421-6. PubMed PMID: 8017841.
15: Han I, Nguyen T, Yang LY, Khokhar AR, Perez-Soler R. Cellular accumulation and DNA damage induced by liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum+ ++(II) in LoVo and LoVo/PDD cells. Anticancer Drugs. 1994 Feb;5(1):64-8. PubMed PMID: 8186432.
16: Perez-Soler R, Francis K, al-Baker S, Pilkiewicz F, Khokhar AR. Preparation and characterization of liposomes containing a lipophilic cisplatin derivative for clinical use. J Microencapsul. 1994 Jan-Feb;11(1):41-54. PubMed PMID: 8138874.
17: Han I, Ling YH, al-Baker S, Khokhar AR, Perez-Soler R. Cellular pharmacology of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum(II) in A2780/S and A2780/PDD cells. Cancer Res. 1993 Oct 15;53(20):4913-9. PubMed PMID: 8402681.
18: Christian MC. The current status of new platinum analogs. Semin Oncol. 1992 Dec;19(6):720-33. Review. PubMed PMID: 1462169.
19: Perez-Soler R, Khokhar AR. Lipophilic cisplatin analogues entrapped in liposomes: role of intraliposomal drug activation in biological activity. Cancer Res. 1992 Nov 15;52(22):6341-7. PubMed PMID: 1423280.
20: Khokhar AR, al-Baker S, Perez-Soler R. Toxicity and efficacy studies on a series of lipid-soluble dineodecanoato(trans-R,R- and trans-S,S-1,2-diaminocyclohexane) platinum (II) complexes entrapped in liposomes. Anticancer Drugs. 1992 Apr;3(2):95-100. PubMed PMID: 1525398.
21: Vadiei K, Siddik ZH, Khokhar AR, al-Baker S, Sampedro F, Perez-Soler R. Pharmacokinetics of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) and cisplatin given i.v. and i.p. in the rat. Cancer Chemother Pharmacol. 1992;30(5):365-9. PubMed PMID: 1505075.
22: Sugarman SM, Perez-Soler R. Liposomes in the treatment of malignancy: a clinical perspective. Crit Rev Oncol Hematol. 1992;12(3):231-42. Review. PubMed PMID: 1497823.
23: Khokhar AR, al-Baker S, Brown T, Perez-Soler R. Chemical and biological studies on a series of lipid-soluble (trans-(R,R)- and -(S,S)-1,2-diaminocyclohexane)platinum(II) complexes incorporated in liposomes. J Med Chem. 1991 Jan;34(1):325-9. PubMed PMID: 1992134.
24: Perez-Soler R, Lopez-Berestein G, Lautersztain J, al-Baker S, Francis K, Macias-Kiger D, Raber MN, Khokhar AR. Phase I clinical and pharmacological study of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II). Cancer Res. 1990 Jul 15;50(14):4254-9. PubMed PMID: 2364384.
25: Perez-Soler R, Lautersztain J, Stephens LC, Wright K, Khokhar AR. Preclinical toxicity and pharmacology of liposome-entrapped cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II). Cancer Chemother Pharmacol. 1989;24(1):1-8. PubMed PMID: 2720887.
26: Khokhar AR, al-Baker S, Krakoff IH, Perez-Soler R. Toxicity and antitumor activity of cis-bis-carboxylato(trans-R,R-1,2-diaminocyclohexane) platinum(II) complexes entrapped in liposomes. Cancer Chemother Pharmacol. 1989;23(4):219-24. PubMed PMID: 2647311.
27: Khokhar AR, Al-Baker S, Perez-Soler R. Toxicity and anti-tumor activity of hydrophobic diammine and diaminocyclohexane platinum complexes entrapped in multilamellar vesicles. Anticancer Drug Des. 1988 Dec;3(3):177-84. PubMed PMID: 3207465.
28: Perez-Soler R, Yang LY, Drewinko B, Lauterzstain J, Khokhar AR. Increased cytotoxicity and reversal of resistance to cis-diamminedichloro-platinum(II) with entrapment of cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in multilamellar lipid vesicles. Cancer Res. 1988 Aug 15;48(16):4509-12. PubMed PMID: 3396003.
29: Lautersztain J, Perez-Soler R, Turpin J, Khokhar AR, Siddik ZH, Schmidt K, Lopez-Berestein G. Cellular pharmacology of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in mouse resident peritoneal macrophages, Kupffer cells, and hepatocytes. Cancer Res. 1988 Mar 1;48(5):1300-6. PubMed PMID: 3342409.
30: Khokhar AR, Wright K, Siddik ZH, Perez-Soler R. Organ distribution and tumor uptake of liposome entrapped cis-bis-neodecanoato trans-R, R-1,2 diaminocyclohexane platinum (II) administered intravenously and into the proper hepatic artery. Cancer Chemother Pharmacol. 1988;22(3):223-7. PubMed PMID: 3409456.
31: Perez-Soler R, Khokhar AR, Lopez-Berestein G. Treatment and prophylaxis of experimental liver metastases of M5076 reticulosarcoma with cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) encapsulated in multilamellar vesicles. Cancer Res. 1987 Dec 15;47(24 Pt 1):6462-6. PubMed PMID: 3315188.
| Chemical | |
|---|---|
| CAS Num | 114488-24-3 |
| Chemical Formula | C26H52N2O4Pt |
| Molecular Weight | 651.8 |
| IUPAC Chemical Name | cyclohexane-1,2-diamine; 7,7-dimethyloctanoate; platinum(+2) |
| Exact Mass | 651.35748 |
| Elemental Analysis | C, 47.91; H, 8.04; N, 4.30; O, 9.82; Pt, 29.93 |
| Synonym | Aroplatin |
| Solubility | Soluble in DMSO, not in water |
| SMILES Code | CC(C)(C)CCCCCC(O[Pt-2]1(OC(CCCCCC(C)(C)C)=O)[NH2+]C2C([NH2+]1)CCCC2)=O |
| Biological | |
| Targets and Effects | bis-neodecanoate diaminocyclohexane platinum |
| 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 | >5 years if stored properly |
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