2) Recent Results

Plants have numerous phytochemicals rich in diversity, some of which regulate plant growth. We investigate on identifications and functions of the plant growth regulators, especially concerning crop productions. In particular, we focus on when, where, and how the phytochemicals work in the plant body. We are also interested in developments of ecofriendly-agrochemicals by structure-modifications using organic synthetic techniques.
On the other hand, some phytochemicals, such as alkaloids, contribute to our health as drugs. We are also interested in developments of novel medicines by thorough biological activity evaluations and structural modifications of phytochemicals.

KEYWORDS: Natural Products Chemistry, Phytochemistry, Plant Physiology, Medicinal Chemistry, Isolation and Spectral Analyses (NMR, IR, MS, and so on) of Phytochemicals, Organic Syntheses, in vitro and in vivo Bioassay.

 

1) Plant Growth Regulators Project

Radish sown in summer has a short stem (rosette) as a result of inhibition of internode elongation. After winter (vernalization), exclusive stem elongation (bolting) and flowering are induced by endogenous hormonal factors. In cold areas such as Hokkaido, early-spring sowing induces unexpected bolting because of chilliness. Bolted radish contains large amount of inedible fiber, and the amount of sugar in the root decreases. Thus, unexpected bolting causes great damage to the production.
We recently identified the antiboting compound in radish leaves and demonstrated that one of the metabolites (methyl jasmonate) inhibits the bolting of radish. However, methyl jasmonate could not become an adequate bolting inhibitor due to its undesirable effects, such as senescence inducing activity. Thus, we investigated the structure-activity relationship (SAR) study of methyl jasmonate, leading to development of new bolting inhibitor (methyl 3-iso-cucurbate) without undesirable effects.

 

2) Antihypertension and/or Antidementia Drugs Project

Hypertension is currently considered as one of the most serious long-term medical conditions worldwide. Angiotensin I-converting enzyme (ACE), as one of the key-targeting component for hypertension drugs, converts angiotensin I to vasopressor angiotensin II through a catalytic hydrolysis process. Recently ACE has been proven to exist in higher levels in the brain cells of Alzheimer disease patients. Brain-penetrating ACE inhibitors (ACEIs) decreased the impact of Alzheimer disease in elderly hypertensive patients.
It is expected that the inclusion of ACEI-rich foods in meal plans has a potential for the elimination of these health issues. Therefore, we explored the occurrence of ACEIs in food extracts combining ACE inhibition assay with LC/ESIMS quantification analysis, revealing that naturally occurring nicotianamine (NA), ubiquitously present in higher plants, is an important constituent in ACEI active foods. Furthermore, oral administration of NA and NA-rich food extracts improved spatial learning and memory functions in rats, in addition to hypertensive relief in rats. Thus, NA is suggested to be a brain-penetrating ACEI, while the inclusion of NA-rich foods in meal plans will contribute to improve the “quality of life” of patients by relieving hypertension and dementia, such as Alzheimer disease.

The mode of action of NA remains unclear, due to lack of crystallographic data. Then, we performed SAR study to discover that a phenylalanine analog displayed the most potent ACEI activity, corresponding to that of captopril. Additionally, molecular docking studies with Gold program were performed to predict the binding poses of NA and its analog, suggesting that NA and its analogs combine a plausible allosteric site in an area away from the catalytic site in ACE. These results proved a possibility of structural modification of NA to develop antihypertensive drugs.

 

3) Nematode Attractant Project

Damage to garlic (Allium sativum) caused by a nematode Ditylenchus destructor are becoming a serious agricultural hazard, leading to a great loss in garlic production. Once the garlic bulbs are invaded, the pathogenic nematode drastically increases the population along with the rotting of bulbs. It was therefore conceived that nematode attractants are present in the bulbs. Based on this hypothesis, chemical investigations were performed to explore a nematode attractant in A. sativum bulbs, which resulted in the identification of methiin (S-methyl-L-cysteine S-oxide) as an attractant. Bioassay and quantification experiments of methiin in A. sativum bulb extracts led to a conclusion that methiin possesses sufficient potential to attract D. destructor into A. sativum bulbs.