3 research outputs found
On Nietzscheās Concept of āEuropean Nihilismā
<div><p>Aplog-1 is a simplified analog of the tumor-promoting aplysiatoxin with anti-proliferative and cytotoxic activities against several cancer cell lines. Our recent findings have suggested that protein kinase CĪ“ (PKCĪ“) could be one of the target proteins of aplog-1. In this study, we synthesized amide-aplog-1 (<b>3</b>), in which the C-1 ester group was replaced with an amide group, to improve chemical stability <i>in vivo</i>. Unfortunately, <b>3</b> exhibited seventy-fold weaker binding affinity to the C1B domain of PKCĪ“ than that of aplog-1, and negligible anti-proliferative and cytotoxic activities even at 10<sup>ā4</sup>Ā M. A conformational analysis and density functional theory calculations indicated that the stable conformation of <b>3</b> differed from that of aplog-1. Since 27-methyl and 27-methoxy derivatives (<b>1</b>, <b>2</b>) without the ability to bind to PKC isozymes exhibited marked anti-proliferative and cytotoxic activities at 10<sup>ā4</sup>Ā M, <b>3</b> may be an inactive control to identify the target proteins of aplogs.</p></div
StructureāActivity Studies on the Spiroketal Moiety of a Simplified Analogue of Debromoaplysiatoxin with Antiproliferative Activity
Aplog-1, a simplified analogue of tumor-promoting debromoaplysiatoxin,
is antiproliferative but not tumor-promoting. Our recent study has
suggested that local hydrophobicity around the spiroketal moiety is
a crucial determinant for antiproliferative activity. To further clarify
the structural features relevant to the activity, we synthesized two
methyl derivatives of aplog-1, where a methyl group was installed
at position 4 or 10 of the spiroketal moiety. 10-Methyl-aplog-1 (<b>5</b>) bound to the C1B domains of novel PKCs (Ī“, Ī·,
and Īø) with subnanomolar <i>K</i><sub>i</sub> values,
approximately 10ā20 times stronger than aplog-1, and markedly
inhibited the growth of many human cancer cell lines, while 4-methyl-aplog-1
(<b>4</b>) had levels of activity similar to those of aplog-1.
Interestingly, <b>5</b> showed little tumor-promoting activity
unlike the tumor promoter debromoaplysiatoxin. These results suggest
that <b>5</b> is a potent PKC ligand without tumor-promoting
activity and could be a therapeutic lead for the treatment of cancer,
like bryostatins
Total Synthesis and in Vitro Anti-Tumor-Promoting Activities of Racemic Acetophenone Monomers from <i>Acronychia trifoliolata</i>
Six acetophenone derivatives, acronyculatins
I (<b>1</b>),
J (<b>2</b>), K (<b>3</b>), L (<b>4</b>), N (<b>5</b>), and O (<b>6</b>), were recently isolated from <i>Acronychia trifoliolata</i>, and the structure of the known
acronyculatin B (<b>7</b>) was revised. Because of the limited
quantities of isolated products as well as their structure similarity,
racemic acronyculatins IāL, N, O, and B (<b>1</b>ā<b>7</b>) were synthesized to confirm their structures and to obtain
sufficient material for biological evaluation. Trihydroxyacetophenone
was converted to the target compounds by various sequences of hydroxy
group protection, allylation or prenylation, and epoxidation followed
by cyclization. <i>C</i>-Prenylations were carried out by
direct addition of a prenyl group or through 1,3- or 3,3-sigmatropic
rearrangement. The synthesized racemic compounds were evaluated in
an anti-tumor-promoting assay using the EpsteināBarr virus
early antigen (EBV-EA) activation induced by 12-<i>O</i>-tetradecanoylphorbol-13-acetate in Raji cells. All tested compounds
significantly inhibited EBV-EA activation. Especially, racemic acronyculatin
I (<b>1</b>) displayed the most potent inhibitory effects, with
an IC<sub>50</sub> value of 7.3 Ī¼M