Yieh-Ping Wan

Low molecular weight analogs of coenzyme Q as hydrogen acceptors and donors in systems of the respiratory chain

Summary 2,3-Dimethoxy-5-methyl-6-n-pentyl-, -6-n-decyl-, and -6-n-pentadecyl-1,4-benzoquinones were synthesized as analogs of coenzyme Q 1 , Q 2 , and Q 3 , respectively. The 6-substituents of the three pairs of quinones have 5, 10, and 15 carbon atoms. These analogs are more stable than the isoprenoid Qs, and have advantages in biochemical experiments. These low molecular weight analogs have inadequate lipoidal characteristics to simulate the higher molecular weight CoQs including CoQ 10 . However, if lipoidal characteristics are not essential, the pentyl and decyl analogs are highly effective as evidenced by their functioning like CoQ 1 and Q 2 as hydrogen acceptors with ETPH particles for oxidative phosphorylation at site I, and after reduction as hydrogen donors for complex III.

Partial reactivation of impaired immune competence in aged mice by synthetic thymus factors.

Abstract Our results clearly show the profound impairment of the humoral, hemolytic, primary, immune response in aged mice (22 months) as compared with this response in young (10 weeks) mice. A partial but significant reactivation of the age-determined impairment of the immunological responsiveness results from subcutaneous administration of two newly synthesized thymus factors and one analog. These synthetic thymus peptide factors correspond to factors previously isolated and identified in thymus glands or blood.

[57] Coenzyme Q and analogs for coenzymic activity

Publisher Summary This chapter focuses on the coenzyme Q and the analogs for coenzymic activity. The form of coenzyme Q in human tissue is coenzyme Q 10 . Many mammalian species also contain coenzyme Q 10 (CoQ 10 ), but some rodents such as rats and mice may contain both coenzymes Q 9 and Q 10 (VII). In nature, coenzymes Q 1 through Q 10 exist, but coenzymes Q 1 , Q 2 , Q 3 , and Q 4 exist in “microtrace” concentrations and were identified by high-sensitivity mass spectrometry in chromatgraphically “pure samples” of the dominant coenzyme Q of diverse organisms. The lipoidal nature of the analogs permits simulation of the intrinsic CoQ 10 for both coenzymic activity and for inhibition. However, a form or analog of CoQ 10 with negligible or minimal lipoidal character, and an assay system that is not responsive to the lipoidal analogs and forms of CoQ, can give very useful biochemical information. Such information may or may not bear directly on the intrinsic role of the dominant form of CoQ in the given species—for example, CoQ 6 or Q 7 in yeast, CoQ 8 in E. coli , CoQ 10 in mammalian mitochondria, etc.

An antiovulatory decapeptide of higher potency which has an L-amino acid (Ac-Pro) in position 1☆

Ac-[Pro1, D-Phe2, D-Trp3, D-Trp6]-LH-RH completely inhibited ovulation in cycling rats at 200μg/rat and is comparable in activity to the corresponding D-<Glu1-analogue. This Ac-Pro1-analogue is the most potent antiovulatory peptide yet known having an L-amino acid residue in position 1. This result shows that for the design of potent inhibitors of ovulation, a D-amino acid residue is not essential in position 1. The corresponding Ac-D-Pro1- and Kic1-analogues completely inhibited ovulation at 750μg/rat, but not at 200μg/rat, and the Cpc1-analogue was inactive at these dosages.

Studies on inhibition of the luteinizing hormone-releasing hormone by an irreversible inhibitor at the receptor site

Abstract [Leu 2 , Leu 3 , D-Ala 6 ]-LHRH is an analog of pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 (LHRH) and inhibits the release of LH and FSH induced by LHRH. This analog and inhibitor has been modified with the objective of developing an active-site-directed irreversible inhibitor. The modification consisted of replacing 1 with Chl 1 which is the moiety of chlorambucil (a nitrogen mustard). The Chl analog inhibited the release of LH and FSH by LHRH after addition prior to LHRH and after three changes of the incubation medium; in contrast, [Leu 2 , Leu 3 , D-Ala 6 ]-LHRH and [des-His 2 ]-LHRH only inhibit release when added together with LHRH. The Chl analog released LH and FSH but not TSH or GH, indicating that its agonist and antagonist activities could be specific at the receptor site for LHRH.

Synthesis of the facteur thymique serique and an analog also related to thymopoietin

Abstract The known 9-amino-acid sequence of the facteur thymique serique (FTS) and the known 49-amino-acid sequence of thymopoietin, in conjunction with background peptide chemistry, raised the possibility that Gln 1 of FTS might be linked to Arg 49 of thymopoietin in a new 58-amino-acid peptide in tissue. A presumed cleavage between Gln 50 and Arg 49 adjacent to the Lys 48 -Arg 49 moiety would liberate [H-Gln 1 ]-FTS and thymopoietin; the former fragment would cyclize to FTS by known chemistry. To study this possibility, FTS, and a new dodecapeptide consisting of Val-Lys-Arg linked to the N-terminal of [H-Gln 1 ]-FTS were synthesized on a new solid-phase resin and were found to show comparable immune stimulating activity, in vivo . These data do not negate, but support, the concept of the 58-aminoacid peptide.

Study of a possible structural relationship between thymopoietin and the facteur thymique serique.

Background peptide chemistry, and the known 49-amino acid sequence of thymopoietin and the known 9-amino acid sequence of the facteur thymique serique (FTS) allowed the concept that Arg49 of thymopoietin might be linked to Gln1 of FTS in a new 58-amino acid peptide in tissue. Cleavage between Arg49 and Gln50 adjacent to the unique Lys48-Arg49 moiety could liberate thymopoietin and the [H-Gln1]-FTS which could cyclize to FTS by the known reaction. In support of, rather than negating, this concept, synthetic FTS and the new dodecapeptide consisting of Val-Lys-Arg linked to the N-terminal of [H-Gln1]-FTS showed comparable immune stimulating activity, in vivo; both peptides appeared more active than synthetic thymopoietin II.

On the importance of position one of ovulation inhibitors, as based on studies on [D-Phe2, Pro3, D-Phe6]-LHRH.

Substitution of cyclopentylcarbonyl-(Cpc) for <Glu1 in the effective and potent antiovulatory inhibitor, [D-Phe2, Pro3, D-Phe6]-LHRH (I) retained the in vitro potency. We know of no other inhibitor of the luteinizing hormone releasing hormone (LHRH) with a modification at position 1, which is as potent in vitro. This result agrees with the concept of the role of <Glu for agonist activity in a low energy conformer of LHRH, and underscores the importance of position 1. [Cpc1, D-Phe2, Pro3, D-Phe6]-LHRH did not inhibit ovulation in rats at the same dosage as did I; this result is under study to circumvent. Des-Gly10-[D-Phe2, Pro3, D-Phe6]-LHRH ethylamide and [Glu1, D-Phe2, Pro3, D-Phe6]-LHRH were significantly less active in vitro than I.

Acidic analogs of the luteinizing hormone-releasing hormone and conformational aspects for activity.

[Gly1a]-LHRH acid (<Glu-Gly-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-OH), [Gly2a]-LHRH acid (<Glu-His-Gly-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-OH), and [Tyr3, Trp5]-LHRH acid (<Glu-His-Tyr-Ser-Trp-Gly-Leu-Arg-Pro-Gly-OH), were synthesized; they released LH with potencies of <0.0003, 0.0003, and 0.0003%, respectively, that of LHRH, but did not act as inhibitors up to a 30,000-fold relative dosage. Absence in these analogs of “conformational components” involving a hydrogen bond between the <Glu1 and Ser4 as proposed for LHRH and/or the proposed parallel planarity of the Trp-Tyr aromatic nuclei, and other effects including that of a C-terminal acid, could explain the observed data.