Esters of cyclic ADP ribose derivatives

Details Esters of cyclic ADP ribose derivatives Esters of cyclic ADP ribose derivatives

2002-06-20

2004-11-02

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S026200, C536S026210, C536S026220, C536S026230, C536S026710, C536S123130, C536S124000, C536S127000

Reexamination Certificate

active

06812342

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to the field of organic chemistry in general and specifically to the preparation of hydrophobic derivatives of cyclic ADP ribose.
BACKGROUND OF THE INVENTION
Intracellular calcium plays key roles in stimulation-secretion coupling in pancreatic islet &bgr;-cells. The elevation of cellular cytosolic calcium concentration ([Ca
2+
]
c
) is mediated through two pathways: Ca
2+
release from intracellular calcium stores and Ca
2+
influx from extracellular medium. The mechanisms underlying internal calcium release in &bgr;-cells remain incompletely understood, and the relative contribution of intracellular Ca
2+
release to the overall [Ca
2+
]
c
increase and subsequent insulin secretion needs to be determined.
Ca
2+
release from intracellular stores is an important signaling mechanism for a variety of cellular processes and is generally controlled by two systems, the IP
3
and cADPR systems (FIG.
1
). IP
3
acts directly on the IP
3
receptor (IP3R) localized in the endoplasmic reticulum (ER). IP3R forms the Ca
2+
releasing channel and regulates the efflux of Ca
2+
from the ER to the cytosol. Cyclic ADP ribose increases the opening probability of other intracellular Ca
2+
releasing channel formed by the ryanodine receptor (RyR) in the ER.
Ca
2+
influx through voltage gated Ca
2+
channels is a well-characterized phenomenon in &bgr;-cells, and it is thought to play an important role in maintaining Ca
2+
homeostasis, especially during glucose stimulation. However, contributions from internal calcium release cannot be ignored. Ca
2+
influx from extracellular sources and Ca
2+
release from the intracellular pool in human &bgr;-cells has been examined, and showed that 42-75% of the increase in intracellular Ca
2+
by glucose stimulation was due to the release of Ca
2+
from the intracellular stores. Both IP
3
and cADPR signaling systems have been reported in insulin secreting &bgr;-cells, but controversies remain regarding which system is more important for maintaining proper insulin secretion responses.
To examine IP
3
or cADPR induced Ca
2+
release in &bgr;-cells, it is necessary to deliver these second messengers inside cells and assay their effects on cellular calcium homeostasis and insulin secretion. Methods relying on triggering cell surface receptors to produce endogenous IP
3
or cADPR inevitably activating other signaling pathways, making it impossible to separate the effects caused by IP
3
or cADPR from those caused by other signaling branches. To deliver exogenous IP
3
or cADPR inside cells, one need to overcome the difficulty of getting them across cell membranes. Both IP
3
and cADPR are charged and hydrophilic molecules at physiological pH, thus are membrane impermeant. Previous techniques of getting these two molecules across hydrophobic cell membranes include microinjection, patch clamping, electroporation or detergent assisted permeabilization. All these methods are invasive and suffer from major drawbacks such as disrupting intact cell membranes, letting cytosolic factors leak out of cells, and compromising long term viability of cells. In addition, techniques such as microinjection or patch clamping can only be applied to single cells, making it practically impossible to study more physiological preparations such as islets.
SUMMARY OF THE INVENTION
One form of the present invention is a hydrophobic compound of the general formula:
where R
1
, R
2
, R
3
and R
4
are each independently hydrogen or linear or branched alkyl groups having from 1 to 12 carbon atoms. R
5
and R
6
are each an alkyl group, metallic cation, a photo-labile caging group, or an acyloxymethylgroup or a homologue thereof. W is CH
2
, CF
2
, or CHF. X is N or CH. Y is N or CH. Z is chosen from the group including H, Br, NH
2
, OCH
3
, CH
3
and N
3
.
Another form of the invention is a method for preparing a hydrophobic composition comprising the following steps:
where RO and R′O comprise independently in each location carboxylate groups further comprising from 2 to 20 carbon atoms.


REFERENCES:
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patent: 5608047 (1997-03-01), Sih
patent: 5834436 (1998-11-01), Tsien et al.
patent: 5866548 (1999-02-01), Tsien et al.
patent: 5872243 (1999-02-01), Gee et al.
patent: 5955453 (1999-09-01), Tsien et al.
patent: 5980862 (1999-11-01), Meade et al.

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