Molecule of the Week (06)
The molecule of the week originates from research at the Indian Institute of Science dealing with the photoactivation of oxovanadium complexes for photodynamic therapy (Sasmal, P.K.; Patra, A.K.; Nethaji, M. Chakravarty, A.R. Inorg. Chem. 2007, 46, 11112 – 11121). Photodynamic Therapy (PDT) is an anti-tumor therapy where the anti-tumor drug is activated by irradiation of the tumor with light. There are a couple of characteristics necessary for a potential PDT drug. The first is that it cannot exhibit any ‘dark’ activity; that is, it cannot be active without first being irradiated with light. The second is that the excitation wavelength should be as close to IR as possible. This allows for the light to penetrate the skin without damaging the healthy cells, which UV light would do. The oxovanadium complex in this research is the first vanadium complex to fulfill both of these requirements.
The mechanism of action is extremely interesting. The ligands on the vanadium first bind to the minor groove of the DNA. The complex is then irradiated with light, which activates the metal complex. The activation of the metal complex allows it to transform triplet oxygen, 3O2, into singlet oxygen, 1O2. Singlet oxygen is highly reactive and will react with any molecule in proximity, which in this case is DNA. The destruction of DNA by singlet oxygen leads to cell death even in tumor cells, allowing for the targeted destruction of tumors while leaving healthy cells intact. The only question I have is how molecules like this are metabolized in vivo. Would they stay bound to the DNA of healthy cells for an indefinite period of time and how would their presence affect the activity of cell machinery? Questions such as this need to be addressed, but the groundbreaking research done here is still vital to the search for anti-tumor drugs.
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Pretty cool Paul! My question is of selectivity, or is that where the amino acid side chain comes into play?
I am pretty sure there really is no ‘selectivity’ in the normal sense for this molecule: you just want something that will bind DNA. I think the selectivity comes from the human control of the irradiation – after that it will (hopefully) deal irreparable damage to all of the DNA in the cell. Is that what you mean? It’s kinda like a spray-and-pray tactic combined with super-precise activation.
I’m referring to specificity of ‘binding’ to the DNA wrt the base pairs, i.e., is there selectivity to a specific base pair and does the amino acid side chain contribute to the specificity. And does it actually bind or does it intercalate into the DNA strand?
Very good question. The molecule binds through the minor groove of the DNA, where there is little specificity for interactions. This is because cytosine and thymine present the same hydrogen bonding partners. The ‘unique’ hydrogen bonding partners are found on the major groove side. Additionally, the molecule really isn’t large enough to have a large sequence specificity – which means that if it does preferentially bind to a sequence, it will be short enough that it’s most likely repeated around the genome.