Solveig მადლობა განმარტებისთვის,
ბუფერულ მექანიზმზე მეც მსმენია, ორგანიზმს აქვს .
ხო ეხლა კონკრეტულად აცეტოგენინებს რაც შეეხება: იმუნო მასტიმულირებელი ეფექტიც აქვთ , აი შეხედეთ რა წერია: >
Annonaceous acetogenins are waxy substances consisting of C32 or C34 long chain fatty acids which have been
combined with a propan-2-ol unit at C-2 to form a gama-lactone. They are only found in several genera of the
plant family, Annonaceae. Their diverse bioactivities as antitumour, immunosuppressive, pesticidal,
antiprotozoal, antifeedant, anthelmintic and antimicrobial agents have attracted more and more interest
worldwide. Recently, we reported that the Annonaceous acetogenins can selectively inhibit the growth of
cancerous cells and also inhibit the growth of adriamycin resistant tumour cells.
1
As more acetogenins have
been isolated and additional cytotoxicity assays have been conducted, we have noticed that, al(hough most
acetogenins have high potencies among several solid human tumour cells lines, some of the derivatives within
the different structural types and some positional isomers show remarkable selectivities among certain cell
lines, e.g. against prostate cancer (PC-3).
2
We now understand the primary modes of action for the acetogenins. They are potent inhibitors of NADH :
ubiquinone oxidoreductase, which is an essential enzyme in complex I of the electron transport system (ETS)
which eventually leads to oxidative phosphorylation in mitochondria.
3-5
A recent report showed that they act
directly at the ubiquinone catalytic site(s) within complex 1 and in microbial glucose dehydrogenase.
6
They also
inhibit the ubiquinone-linked NADH oxidase that is peculiar to the plasma membranes of cancerous cells and
functions to permit cytosolic phosphorylation (substrate level phosphorylation) by restoration of NAD levels.
Thus, the end result of both of these mechanisms is ATP deprivation.
7
მოქმედების პრინციპი ახნილია, ჩვეულებრივ და სიმსივნურ უჯრედებს აქვთ, განსხვავებული მექანიზმი ატფ წარმოქმნის : კონკრეტულად კი იყენებს NADH ამ ფერმენტს
და ამის საშუალებით ხდება ატპ ს მიღება. ამ ნივთიერებათა ჯგუფი კი აფერხებს ამ ფერმენტის მოქმედებას
რეზისტენტულ სიმსივნის უჯრედს ქონია რაღაც პომპის მსგავსი რომლის საშუალებითაც გამოაქვს მასში მოხვედრილი უცხნო სხეული, ნივთიერება ;
ამ პომპის ასამოქმედებლად კი საჭიროა ისევ ატპ და NADH ფერმენტი ; ამით ხსნია იმას რომ რეზისტენტულ უჯრედებს კარგად ებრძვის
და სიმსივნის უჯრედი თვითლიკვიდაციას განიცდის , აპოტოფსის , დაპროგრამებულ თვითმკვლელობას
მგონი სწორად ვთარგმნე
დღეს უნდა გამოვიწერო ექსტრაქტი , გავტესტო უნდა
თესლებიც იყიდება , რაც ვნახე ჩვენ კლიმატურ პირობებში რომ იხაროს არის შანსი, უნდა დავრგო აუცლიბლად
უფრო ვრცლად :>
The structure—activity relationships (SARs) of twenty diverse Annonaceous acetogenins in the inhibition of
oxygen uptake in the rat liver mitochondrial assay
77
were explained in our last review.
20
This SAR work has
now been extended to include thirteen additional compounds.
78
The latter study examined new structurally
diverse compounds that have been recently isolated. A positive control of bullatacin 126 was examined during
every separate determination so that the data could be both normalized to this value and compared in a
bullatacin index' (Table 3) thereby limiting day to day, rat to rat, and other variabilities that are inherent in an
assay of this nature.
The results (Table 3) show that two compounds, trilobin 164 and asiminacin 109, are both more active than
bullatacin 126. Also, the new structural type having a hydroxylated tetrahydropyrane ring (THP), mucocin 207,
was nearly as active as bullatacin 126. With non-adjacent bis-THF ring compounds, such as aromin 205,
separation by more than 4 carbons between the rings caused a decrease in potency to that of a mono-THF ring
acetogenin. With two virtually identical mono- THF ring acetogenins, asiminenin A 56 vs asiminenin B 40, the
latter, with a trans THF ring, was approximately four times more potent than the former, with a cis THF ring.
The mitochondrial assay measures activity at the sub-cellular level which, of course, does not address
absorption, protein binding, metabolism, excretion and transport across cellular membranes.
In several recent papers, some acetogenins appear to be selectively cytotoxic for certain cancer types; altered
biological transport or slight variations in receptor geometry in the membranes of such cell lines might explain
these selectivities, and we hope to be able to have these compounds tested in the larger panel of human tumour
cell lines at the National Cancer Institute. Longicin 57, a mono-THF ring compound, shows a potent ED50 value
of 1.25 x 10
-9
ppm in PaCa-2 cells (human pancreatic carcinoma) ;
27
longicoricin, another mono-THF ring
acetogenin, showed a selective ED50 of < 1 x 10
-
' ppm in PC-3 cells (human prostate adenocarcinoma)."
Usually, the mono- THF ring acetogenins show much reduced levels of cyto- toxicities in cell cultures. Trilobacin 163, while not being very active against A-549 or MCF-7 cells (human lung and human breast
carcinomas, respectively) had an ED50 of < 1 x 10
-
" in HT-29 cells (human colon carcinoma); trilobin, a
trilobacin analogue with the 4-OH shifted to the 10 position, was more generally cytotoxic but extremely potent
in all cell lines.59 cisAnnonacin 54 also showed a surprising selectivity (ED50 of 1.0 x 10
-8
ppm) against HT-29
cells (colon carcinoma).
73
Squamotacin 123, with the hydroxylated bis-THF ring system of bullatacin 126 shifted from C-15 to C-13, and
its 35 carbon counterpart, molvizarin 117, both exhibited significant selective cytotoxicities against PC-3
(prostate) cells (on the order of ED50 1 x 10
-8
ppm) with only moderate toxicity to the five other cell lines.
2
Similarly, longimicin D 103, with the bis-THF ring system of asimin 107 shifted from C-15 to C-13, showed an
ED50 value of 1.69 x 10
-7
ppm against PaCa-2 (pancreatic) cells.
29
The new structural type, mucocin 207, with
its hydroxylated THP ring, had significant cytotoxicity to both the PaCa-2 and A-549 cell lines (pancreatic and
lung carcinomas, respectively), while its formaldehyde acetal derivative was only toxic to the A-549 cells.
31
In
all of the above studies, which are from our laboratories, adriamycin, a standard anticancer agent, was always
run as a positive control and consistently showed nonselective cytotoxicities at ED50 values ranging from 10
-1
to
10
-3
ppm with variation between runs of not greater than two orders of magnitude (10 to 100 times).
A notable point in these comparisons is that slight variations in structure may lead to significant variability in
bioactivities.
39,20
Additional in vivo studies
4
are sorely needed to verify such in vitro selectivities. These
observations serve to demonstrate the necessity and merit of a search for new structural themes in this rapidly
growing class of compound. Less than thirty Annonaceous species have yielded more than 220 acetogenins;
there are undoubtedly many more diverse compounds to be found among the > 2000 various species in this
family.
79
Some of these compounds will be optimum in structure for specific tumour types and various other
uses.
ამ ჯგუფში შედის 2000 ზე მეტი ნივთიერება და ამის გაუჭირდება სიმსივნის უჯრედს რეზისტენტულობის გამომუშავება ყველას მიმართ