Replies to post #75151 on Biotech Values

[poorgradstudent]

THLD:

>They may sound like they are similar because they phosphoramidate conjugates, but the active drugs in fact are very different. If you wanted to compare TH-302 to something - Ifosfamide would be the closest comparison. Ifosfamide is what they based the active part of TH-302 on and ifos is a widely accepted chemotherapy drug.<

The phosphorodiamidate is the active alkylating drug. If you go to Figure 1 of the following link, you'll find the active alkylating derivative of ifosfamide:

Ifosfamide

It is the one labeled "ifosforamide mustard." It is, generally, a phosphorodiamidate alkylator. TH-302 is described as a Br substituted version rather than the Cl substituted version. Therefore, TH-302's active moeity is also a phosphorodiamidate alkylator, substituted with Br instead of Cl as seen for ifosfamide Figure 1 above.


Now if you would click on the below link and follow it to page 418, you will see the active phosphorodiamidate alkylating derivative of canfosfamide (Telcyta):

Canfosfamide / Telcyta

You will see that there is not much difference between the phosphorodiamidate alkylators that are the active derivatives of canfosfamide / Telcyta and ifosfamide. And despite the substitutions in the chemical structure, the mechanisms of action for the active agents are identical (they're all alkylators and work to hit DNA).

>And the active compounds are very different.<

The chemical structures and methods of action of the two do not support this claim. I do hope it is clear that it is the phosphorodiamidate alkylator structure that is the "active" form. Ifosfamide and canfosfamide both are precursors to the substituted phosphorodiamidate that is the active alkylator agent for both drugs. Since TH-302 is based on ifosfamide, and it's active moiety is basically a Br substituted version of the ifosfamide derived phosphorodiamidate alkylator, those two are closely equivalent. The chemical structures I've linked to for the phosphorodiamidate alkylators derived from ifosfamide and canfosfamide show that these are as similar as can be for two drugs that are in the same class, chemically very similar but not identical, and share the same mechanism of action. Think taxol and taxotere.

>I think it’s very naive or perhaps ill informed to say Telcyta and TH-302's drugs are anything alike except in the fact they share a base in a phosphoramidate conjugates. It's like saying water and hydrochloric acid are similar because they both share a hydrogen base.<

Let's not make this personal. Unless you're a chemist by trade, I don't think you should be calling me naive and ill-informed. If you would like to explain why a Br substituted phosphorodiamidate alkylator (from TH-302) will do things that a Cl substituted phosphorodiamidate alkylator (from ifosfamide)will not, and why that will be different than another Cl substituted phosphorodiamide alklylator (from canfosfamide), then I would be appreciative of the explanation.