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P-2170 4α-Phorbol 12,13-Didecanoate, >99%

[4α-PDD] [4a-Phorbol 12,13-Didecanoate] [4a-PDD] [4a Phorbol 12,13-Didecanoate] [4a PDD] [4α PDD] [4alpha Phorbol 12,13-Didecanoate] [4alpha PDD]

M.W. 672.93

C40H64O8

[27536-56-7]

Storage:  Store at or below -20 ºC.  Solubility:  Soluble in DMSO or ethanol.  Disposal:  A

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• Negative control for studies with Phorbol 12,13-Didecanoate, formerly our Cat. No. P-1925, for example, see Trewyn, R.W. and Gatz, H.B.  "Altered growth properties of normal human cells induced by phorbol 12,13-didecanoate."  In Vitro. 20:  409-15 (1984).

• Please request Technical Note #13 for additional information.

• 4α-PDD Activation of TRPV4 Channels  Long thought to be a biologically inactive or extremely weak phorbol ester analog (i.e., an ED50 >25 µM for binding to protein kinase C), 4α-PDD has now been shown to be a reasonably potent activator of two TRPV4 channels, namely human VRL-2 and murine TRP12 channels [Watanabe, H., et al.  "Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives."  J. Biol. Chem. 277:  13569-13577 (2002)].  The ED 50 of 4α-PDD for activation of the TRP12 channel was ~400 nM, and for increasing internal calcium levels in 1321N1 astrocytoma cells expressing human VRL-2, the ED50 of 4α-PDD was ~185 nM.  This work extends earlier results showing non-phorbol-ester-like effects of 4α-PDD [Reeve, H., et al.  "Enhancement of Ca2+ channel currents in human neuroblastoma (SH-SY5Y) cells by phorbol esters with and without activation of protein kinase C."  Pflugers Arch. Eur. J. Physiol. 429:  729-737 (1995)] and 4α-phorbol 12,13-dibutyrate (4 -PDBu) [Doerner, D., et al.  "Protein kinase C-dependent and -independent effects of phorbol esters on hippocampal calcium channel current."  J. Neurosci. 10:  1699-1706 (1990)] on calcium currents.

  Because 4α-PDD has few, if any, recognized biological effects at sub-micromolar concentrations other than these effects on TRPV4 channels, Watanabe et al. certainly seem justified in stating that "4α-PDD can be used as a robust and reliable tool to study several features of TRPV channels and to probe functional effects of the activation of this channel in in vivo systems".  That said, it is also important to note that absolute selectivity of 4α-PDD for activating TRPV4 channels has not been demonstrated.  Though 4α-PDD has been shown over the years to have little or no effect in a fairly wide range of biological assays, 4α-PDD might prove to have other, as-yet-unidentified activities if subjected to more extensive testing against various targets.

  [As an aside, we point out that reference #25 in the Watanabe article, cited in support of the inactivity of 4α-PDD on PKC, appears not to contain any mention at all of 4α-PDD or other 4α-phorbol esters.  For the convenience of those who are preparing manuscripts dealing with 4α-phorbol esters, one or more appropriate references supporting the low activity of these compounds on PKC will be added to this LC Labs product description shortly.]

  [Also, see below for an important note about nomenclature.  Technically, 4α-PDD is not a phorbol ester, it is a 4α-phorbol ester — a small but important distinction — and must always be specified as such to avoid confusion with the dramatically different properties of the phorbol esters.]

  Surprisingly (in view of historical structure-activity data), PMA (phorbol 12-myristate 13-acetate), the classical nanomolar-potency PKC activator, was 10- to 50-fold weaker than 4α-PDD for activation of the TRPV4 channels.  If both PMA and 4α-PDD were targeting a PKC-related protein, via a mechanism fundamentally similar to that of classical PKC activation by phorbol esters, PMA would be expected to be many orders of magnitude more potent than 4α-PDD.  Watanabe et al. tested a wide range of PMA and 4α-PDD concentrations, and there appears to be no doubt that the relative potencies expected for PMA and 4α-PDD for classical PKC-related effects are strikingly reversed for the TRPV4 channel activation phenomenon.  Furthermore, in some assays PMA was merely a "partial agonist", showing only 50-65% of the response elicited by 4α-PDD.

  The PMA/4α-PDD potency inversion in turn strongly suggests that 4α-PDD must be acting via a mechanism distinct from the classical interaction of a phorbol 12,13-diester with a phorbol ester/diacylglycerol-type receptor target, such as those found on the PKC family of proteins.  Given the long history and, until now, largely settled picture of the biological properties of phorbol and 4α-phorbol esters, this question of mechanism is of high interest, and the answer(s) might turn out to have a wide impact on several areas of pharmacology.

  LC Laboratories also offers other 4α-phorbol diesters of varying hydrophobicity; these presumably can be used for structure-activity studies of the TRPV4 activation effect.  Specifically, we offer 4α-PMA (Cat. No. P-8880) and 4α-phorbol 12,13-dibutyrate (4α-PDBu; formerly our Cat. No. P-4678) , both of which (especially 4α-PDBu) are less hydrophobic than 4α-PDD.

  These analogs of 4α-PDD have considerable potential utility.  The high hydrophobicity (high lipid partition coefficient) of 4α-PDD makes it quite soluble in cellular membrane compartments, and it is reliably presumed to be very difficult to wash this compound out of membrane preparations or cell cultures.  4α-PMA and 4α-PDBu may prove to be less potent than 4α-PDD, but if they retain sufficient potency vis-a-vis 4α-PDD, they might be preferable as research tools because of their enhanced potential to equilibrate among aqueous and lipid cellular compartments and to be washed out of experimental preparations.

  In the past, in addition to 4α-PMA and 4α-PDBu, we have also made some other 4α-phorbol diesters, such as 4α-phorbol 12,13-diacetate, a compound of very low hydrophobicity.  These other 4α-phorbol derivatives are not currently listed as LC Labs products but are available by special request.  We are also pleased to offer all of our 4α-phorbol products in bulk quantities at substantial discounts.

• Chemical Structures. The primary structural difference between 4α-PDD and the highly potent phorbol ester-type PKC activators is the configuration at C4.  In the highly active phorbol ester family, the hydroxy group at C4 is in the β configuration, i. e., rising up out of the two-dimensional structure as viewed on paper or a computer monitor.  The 4-α-phorbol esters such as 4α-PDD, 4α-PMA and 4α-PDBu have the 4-OH group oriented down below the paper or computer screen's two-dimensional plane.

• Nomenclature. Unless "4α" is specified, all "phorbol" compounds are automatically defined, by operation of standard chemical nomenclature conventions, as having the 4β-configuration, as part of the meaning of the word "phorbol."  This is much like the word "cholesterol", which automatically means that its hydroxy group at carbon 3 is in the β configuration; there is no need to specify "3β-cholesterol", whereas a cholesterol derivative with a 3α hydroxy group would require a "3α-cholesterol" specification.  To avoid confusion in this field, it is useful to note that, technically, 4α-PDD is not a "phorbol ester", it is a "4α-phorbol ester", and the structural differences, though minor overall, are quite significant biologically.  Given the extreme differences in their biological properties, both on PKC and TRPV4 channel-based phenomena, efforts to maintain distinctive names for members of these two biologically quite distinct classes of compounds appear to be well justified.

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