Deoxyadenosine (A) is the DNA nucleoside, which pairs with deoxythymidine (T) in double-stranded DNA.
Cladribine is a molecule based on deoxyadenosine. Deoxyadenosine gains a phosphate group due to the action of the target or cladribine called deoxycytidine kinase. Other molecules help the deoxyadenosine to gain three phosphate groups and then it triggers death of B and T cells. This toxic effect is countered by breakdown of deoxyadenosine by a molecule called adenosine deaminase.
cladribine has a simple chlorine (Cl) addition making it resistant to adeosine diaminase and so more likely to be triphophosphorylated (addition of three phosphate (PO4) groups. This causes death of white blood cells and so it can inhibit MS.
Next up you want an alternative for your drug card and the closest look-a-like is a drug called clofarabine. This cladribine with an extra fluorine (F) molecule. This is a simple bit of chemistry that tends to make the drug hang around for abit longer. This is a cancer drug available in the USA .
Clofarabine is sequentially metabolized to the 5’-monophosphate metabolite by
deoxycytidine kinase (sounds like cladribine) and mono- and di-phospho-kinases to the active 5’-triphosphate metabolite. Clofarabine inhibits DNA synthesis also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic (death inducing) mitochondrial proteins, leads to
programmed cell death. (Sounds like cladribine).
Clofarabine is a second-generation purine nucleoside analog designed to overcome biological limitations observed with fludarabine. A 2´(S)-fluorine in clofarabine significantly increased the stability of the glycosidic bond in acidic solution and toward phosphorolytic cleavage as compared to fludarabine. A chlorine substitution at the 2-position prevents deamination. (sounds like cladribine)
Fludarabine Fludarabine inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase
Fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-β-D-arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase (just like the above). Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then phosphorylated inside the cell by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This
metabolite appears to act by inhibiting DNA synthesis.
Vidarabine is used as an anti-herpes drug but is rapidly destroyed by adenosime diaminase unlike cladribine and the others
There are many ways of inhibiting lymphocytes and fludarabine is sometimes used in the HSCT process and fludarabine and chlofarabine kill lymphocytes and cancers. However they also come with a host of side effects and are unproven inproper trials in MS. If people are a cheaper alternative to oral cladribine you could look no further than generic cladribine as was done by ProfK. But there is more to MS drugs than cheap. Governments want innovation and new medicines, cheap is notgoing to give you new ones.
Many years ago we looked at clofarabine in the meeces as a alternative to cladribine and to our surprise it didnt inhibit T cell responses, we then had a look a cladrine and same thing….so you should not use cladribine in mice to see what is going on…Some people have done it….Say-No-More. However the enzyme make up is not quite the same in mice and to get sensible answers from some agents you have to do studies in non-human primates and above.
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