“Draft:RAPTA”的意思、由来-开放百科全书

Ruthenium arene PTA (pta = 1,3,4-triaza-7-phosphatricyclo-[3.3.1.1]decane) derivatives, or RAPTA, is one of the two organoruthenium half-sandwich compound class, an anti-cancer drug candidate along with the ruthenium arene ethylenediamine (RAED) derivatives. Both RAPTA and RAED derivatives are ruthenium (II) complexes, which are different from the two well-known ruthenium anti-cancer drugs NAMI-A and KP1019, which are Ru(III) complexes.

Structure and properties

It is envisaged that RAPTA derivatives have the “piano stool” structure like others organometallics half-sandwich compound, however, their crystal structures have not been determined^[1]. The pta ligand was designed to make the complexes more soluble in water, and the two labile chlorido ligands can exchange to aquo ligand in the presence of water^[2].

Synthesis

In a typical synthesis, [Ru (η⁶-p-cymene)Cl₂] is reacted with 2 equivalents of 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (pta) for 24h under reflux in methanol to yield to [Ru(η⁶-p-cymene)Cl₂(pta)]^[3].

RAPTA derivatives

Several derivatives of RAPTA were synthesized, and two of the most notable are [Ru(η⁶-p-cymene)Cl₂(pta)] (RATPA-C) and [Ru(η⁶-toluene)Cl₂(pta)] (RAPTA-T).

Mode of action

At first, RAPTA was anticipated to hydrolyse and interact with DNA to target primary tumor, which is similar to the platinum analogue cisplatin. Studies showed that adducts were form between RAPTA compounds and protein (especially cathepsin B and thioredoxin reductase(TrxR))^[4]^,^[5]. Moreover, the reactivity of RAPTA in the presence of protein was totally different than that of cisplatin^[6]. In vitro studies showed that cytotoxicity of RAPTA derivatives was much less as compared to cisplatin, and some RAPTA compounds are not even cytotoxic to healthy cells^[7]. Surprisingly, both RAPTA-C and RAPTA-T showed the ability to inhibit lung metastasis in mice bearing middle cerebral artery mammary carcinoma (by measuring the number and weight of the metastases), whilst having small effect on primary tumor^[8]. The only ruthenium complexe which proves the ability against metastasis was NAMI-A, and this work has high practical application in chemotherapy since the removal of primary tumor can be done through frequent surgery while the number of metastasis treatments are limited^[9].

References

1. ^{{cite journal | last1 = Gasser | first1 = G. | last2 = Ott | first2 = I. | last3 = Metzler-Nolte | first3 = N.| journal = J. Med. Chem | volume = 1 | pages = 3-25 | year = 2011 | title = Organometallic anticancer compounds | doi = 10.1021/jm100020w}}
2. ^{{cite journal |doi=10.1016/j.jorganchem.2010.11.009 |title=Organometallic ruthenium-based antitumor compounds with novel modes of action |year=2011 |last1=Ang |first1=W. |last2=Casini |first2=A. |last3=Sava |first3=G. |last4=Dyson |first4=P. J. |journal=J. Organomet. Chem. |volume=696 |issue=5 |pages=989–98}}
3. ^{{cite journal | last1 = Claire. S | first1 = A. | last2 = Paul | first2 = J. D. | last3 = David | first3 = J. E. | last4 = Sarah | first4 = L. H.| journal = Chem. Commun | volume = 15 | pages = 1396–1397 | year = 2001 | title = [Ru(η⁶-p-cymene)Cl₂(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo- [3.3.1.1]decane): a water soluble compound that exhibits pH dependent DNA binding providing selectivity for diseased cells | doi = 10.1039/B104021A}}
4. ^{{cite journal | last1 = Casini | first1 = A. | last2 = Mastrobuoni | first2 = G. | last3 = Ang | first3 = W. H. | last4 = Gabbiani | first4 = C.| last5 = Pieraccini| first5 = G. | last6 = Moneti| first6 = G. | last7 = Dyson | first3 = P. J. | last8 = Messori | first8 = L.| journal = ChemMedChem | volume = 2 | pages = 631-635 | year = 2007 | title = ESI-MS characterization of protein adducts of anticancer ruthenium(II) arene PTA(RAPTA) complexes | doi = 10.1002/cmdc.200600258}}
5. ^{{cite journal | last1 = Casini | first1 = A. | last2 = Gabbiani | first2 = C. | last3 = Sorrentino | first3 = F. | last4 = Rigobello | first4 = M.P.| last5 = Bindoli| first5 = A. | last6 = Geldbach| first6 = T.J. | last7 = Marrone | first7 = A. | last8 = Hartinger | first8 = C.G. | last9 = Dyson | first9 = P.J. | last10 = Messori | first10 = L. | journal = J. Med. Chem. | volume = 54 | pages = 6773-6781 | year = 2008 | title = Emerging protein targets for anticancer metallo drugs: inhibition of thioredoxin reductase and cathepsin B by antitumor ruthenium(II)-arene compounds. | doi = 10.1021/jm8006678}}
6. ^{{cite journal | last1 = Casini | first1 = A. | last2 = Michelucci | first2 = E. | last3 = Gabbiani | first3 = C.| last4 = Pieraccini| first4 = G. | last5 = Moneti| first5 = G. | last6 = Dyson | first6 = P. J. | last7 = Messori | first7 = L.| journal = J. Biol. Inorg. Chem | volume = 14 | pages = 761-770 | year = 2009 | title = Exploring metallodrug-protein interactions by mass spectrometry: Comparisons between platinum coordination complexes and an organometallic ruthenium compound | doi = 10.1007/s00775-009-0489-5}}
7. ^{{cite journal | last1 = Gasser | first1 = G. | last2 = Ott | first2 = I. | last3 = Metzler-Nolte | first3 = N.| journal = J. Med. Chem | volume = 1 | pages = 3-25| year = 2011 | title = Organometallic anticancer compounds | doi = 10.1021/jm100020w}}
8. ^{{cite journal | last1 = Scolaro | first1 = C. | last2 = Bergamo | first2 = A. | last3 = Brescacin | first3 = L.| last4 = Delfino| first4 = R. | last5 = Cocchietto| first5 = M. | last6 = Laurenczy | first6 = G. | last7 = Gelbach | first7 = T.J.| last8 = Sava | first8 = G | last9 = Dyson | first9 = P.J. | journal = J. Med. Chem. | volume = 48 | pages = 4161-4171 | year = 2005 | title = In vitro and in vivo evaluation of ruthenium(II)-arene PTA complexes. | doi = 10.1021/jm050015d}}
9. ^{{cite journal | last1 = Dyson | first1 = P.J. | last2 = Sava | first2 = G.| journal = Dalton. Trans. | pages = 1929–1933 | year = 2006 | title = Metal-based antitumour drugs in the post genomic era | doi = 10.1039/b601840h}}