Acyclic Alcohols Research Articles

Investigating the pharmacological potential of phytol on experimental models of gastric ulcer in rats.

Phytol is a diterpene constituent of many essential oils, belonging to the group of unsaturated acyclic alcohols. Although phytol possesses antimycobacterial and anti-inflammatory effects, no reports of a gastrointestinal action are available from the literature. Due to the well-known shortcomings of classical anti-ulcer drugs (e.g. side effects or relapses), natural products may offer an attractive alternative. In this study, a potential gastroprotective activity of phytol was evaluated using acute and chronic ulcer models in rats. Phytol 12.5, 25 and 50mg/kg, administered orally 1h prior to induction of gastric lesions by absolute ethanol, inhibited the lesion area by 96, 90 and 95%, respectively. When lesions were induced by ischemia and reperfusion, phytol 12.5 and 25mg/kg per os decreased the lesion areas by 89 and 46%, respectively. In the third acute ulcer model (lesions induced by ibuprofen), phytol 12.5mg/kg reduced the lesion area by 55%. Phytol restored the decreased level of reduced glutathione, the increased levels of myeloperoxidase and malondialdehyde and the decreased levels of catalase and superoxide dismutase in rats with gastric ulcer induced by ethanol to levels obtained in vehicle group. Finally, in a chronic model in which gastric ulcer was induced by acetic acid directly instilled into the stomach, phytol administered orally over a time period of 7 days at 12.5, 25, 50 and 100mg/kg reduced lesion areas by 84, 81, 83 and 68%. Our data suggest a gastroprotective and cicatrizing effect of phytol, possibly associated with its antioxidant effect.

Electrochemical Azo-free Mitsunobu-type Reaction.

The classic chemical Mitsunobu reaction suffers from the need of excess alcohol activation reagents and the generation of significant by-products. Efforts to overcome these limitations have resulted in numerous creative solutions, but the substrate scope of these catalytic processes remains limited. Here we report an electrochemical Mitsunobu-type reaction, which features azo-free alcohol activation and broad substrate scope. This user-friendly technology allows a vast collection of heterocycles as the nucleophile, which can couple with a series of chiral cyclic and acyclic alcohols in moderate to high yields and excellent ee's. This practical reaction is scalable, chemoselective, uses simple Electrasyn setup with inexpensive electrodes and requires no precaution to exclude air and moisture. The synthetic utility is further demonstrated on the structural modification of diverse bioactive natural products and pharmaceutical derivatives and its straightforward application in a multiple-step synthesis of a drug candidate.

Electrochemical Azo‐free Mitsunobu‐type Reaction

AbstractThe classic chemical Mitsunobu reaction suffers from the need of excess alcohol activation reagents and the generation of significant by‐products. Efforts to overcome these limitations have resulted in numerous creative solutions, but the substrate scope of these catalytic processes remains limited. Here we report an electrochemical Mitsunobu‐type reaction, which features azo‐free alcohol activation and broad substrate scope. This user‐friendly technology allows a vast collection of heterocycles as the nucleophile, which can couple with a series of chiral cyclic and acyclic alcohols in moderate to high yields and excellent ee's. This practical reaction is scalable, chemoselective, uses simple Electrasyn setup with inexpensive electrodes and requires no precaution to exclude air and moisture. The synthetic utility is further demonstrated on the structural modification of diverse bioactive natural products and pharmaceutical derivatives and its straightforward application in a multiple‐step synthesis of a drug candidate.

Vasorelaxant effect of (E,E)-farnesol in human umbilical vein ex vivo assays

(E,E)-farnesol is a sesquiterpene acyclic alcohol produced by bacteria, protozoa, fungi, plants, and animals. The literature describes its applications in food, pharmaceutical, and cosmetic industries, and also in the pharmacological context with a vasorelaxant effect. However, its effects on human umbilical vessels remain poorly investigated. Thus, this study aims to investigate, in a new way, the vasorelaxant effect of (E,E)-farnesol in human umbilical veins (HUV) from healthy donors. Rings obtained from isolated HUV were suspended in an organ bath to record their isometric tension in different experimental sections. (E,E)-farnesol (1 μmol/L to 1 mmol/L) promoted vasorelaxant effect in venous preparations contracted by depolarization (KCl 60 mmol/L) or pharmacological agonism (5-HT 10 μmol/L), with EC50 values of 239.9 μmol/L and 424 μmol/L, respectively. In calcium-free solution, this effect was also observable. (E,E)-farnesol was able to suppress contractions evoked by CaCl2 and BaCl2 suggesting a blockade of voltage-dependent (especially L-type) calcium channels. The vasorelaxant efficacy and potency of (E,E)-farnesol were affected in the presence of tetraethylammonium (1 and 10 mmol/L), glibenclamide (10 μmol/L) and BaCl2 (1 mmol/L) indicating a possible involvement of potassium channels (BKCa, KATP and KIR) in this effect. Our data suggest that (E,E)-farnesol has a promising potential to be applicable as a vasodilator in hypertensive conditions in pregnancy that alter HUV reactivity.

Kalanchoe sp. Extracts-Phytochemistry, Cytotoxic, and Antimicrobial Activities.

Kalanchoe species are succulents occurring in tropical regions. They have many biological and pharmacological properties. In this study, the cytotoxic and antimicrobial activities of water and dichloromethane Kalanchoe fractions obtained from ethanol extracts of three Kalanchoe species-K. daigremontiana, K. pinnata, and K. blossfeldiana were estimated. The cytotoxic effect was assessed on human cancer cell lines-ovarian SKOV-3, cervical HeLa, breast MCF-7, and melanoma A375-by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The antimicrobial activity was estimated on selected Gram-positive and Gram-negative bacteria strains and on Candida albicans. The phytochemical analysis of selected Kalanchoe extracts was conducted by LC-QTOF-MS. The obtained results showed that the water fraction of K. blossfeldiana was active both on the tested cancer cells (IC50 values were 28.28 ± 2.76 and 32.51 ± 0.69 µg/mL on HeLa and SKOV-3, respectively) and bacteria strains (MIC values were 16 and 32 µg/mL on S. epidermidis and S. aureus, respectively). The water fraction of K. pinnata also had a significant effect on S. epidermidis and S. aureus, with MIC values of 32 and 64 µg/mL, respectively. The water fraction of K. blossfeldiana triggered a decrease in mitochondrial membrane potential (MMP) and induced cell cycle arrest in the G2/M phase in the SKOV-3 and HeLa cells. This fraction did not significantly increase cellular oxidative stress level. The DPPH and ABTS assays revealed that the water fraction of K. blossfeldiana had a strong antioxidant effect (IC50 was 9.44 ± 0.06 and 3.17 ± 0.1 µg/mL, respectively). The phytochemical analysis of the extracts of K. blossfeldiana and K. pinnata revealed the presence of at least 218 main components. The most frequently occurring were flavonol glycosides (31 metabolites), phenylpropanoids (13 metabolites), gallic acid derivatives (13 compounds), benzoic acid derived compounds (14 metabolites), and acyclic alcohol glycosides (16 compounds). In addition, proanthocyanidins were detected mainly in K. blossfeldiana. The study indicates that the water fraction of K. blossfeldiana has significant biological potential and can be further investigated towards anticancer and antimicrobial application.

Remote Electronic Tuning of Chiral N-Heterocyclic Carbenes.

Our recent efforts to develop novel N-Heterocyclic carbene (NHC)-catalyzed asymmetric reactions are described. During our investigation for development of the acylation reactions via acylazoliums generated by the reactions of NHCs and α-oxidized aldehydes, we have observed significant effects of substitution at a remote site of the carbene carbon of NHCs. In addition, we also observed a significant enhancement of the enantioselectivity by the addition of carboxylate anions. From this observation, we proposed a novel working hypothesis involving a formation of a complex of the substrate and additive to reinforce the recognition of the catalyst for enhancement of the catalytic performance of the asymmetric N-heterocyclic carbene system. By applying this concept, we achieved the kinetic resolutions of both cyclic and acyclic alcohols in excellent enantioselectivities. The effects of the remote substitution were also observed in intramolecular Stetter reaction and intermolecular benzoin reaction. In these reactions, the comparison of the catalytic performance of the NHCs bearing variable remote substitutions provided insights into the reaction mechanism because the remote substitution tuned the electronic nature of NHCs without affecting the steric and electrostatic factors around the reaction site. We also developed an intramolecular benzoin condensation involving two aldehydes, which is challenging to realize. Using the substrates bearing proper protecting groups, we succeeded in the stereo divergent synthesis of a variety of inososes, which are important intermediates for the synthesis of biologically active cyclitols.

Facile synthetic route of TiO2–ZnO heteronanostructure coated by oxovanadium (IV) bis-Schiff base complex as a potential effective homogeneous/heterogeneous catalysts for alcohols redox systems

Oxovanadium (IV) bis-Schiff base complex was synthesized by a facile complexation of 2 molar ratio of 2‑hydroxy-Schiff base ligand (HL) with 1 molar ratio of VO2+ ion giving mononuclear VOL2 complex with a square pyramidal geometry. The structure conformation of HL and its corresponding VOL2 complex was assigned within various spectroscopic tools (IR, UV–vis. Mass spectra), as well as the elemental analyses (EA). The deprotonated 4-OH group in VOL2 caused a successful coating of VOL2 on a mixed oxides of TiO2–ZnO nanoparticles awarding nanocomposite of TiO2–ZnO@VOL2. By applying alternative analytical techniques, the surface morphology and internal structure TiO2–ZnO@VOL2 nanocomposites were investigated compared to that of TiO2–ZnO, i.e. by XRD, FESEM, HR-TEM, EDS and IR spectra), and also with TGA and BET (adsorption–desorption isotherm).The catalytic effectiveness of both homogeneous and heterogeneous catalysts (VOL2 and TiO2–ZnO@VOL2) was examined in the productive oxygenation reactions of BA (benzyl alcohol) by an aqueous hydrogen peroxide under an aerobic environment to the chemo-selective product benzaldehyde (BZ), and benzoic acid (BO), as the overodixation product. Both VOL2 and TiO2-ZnO@VOL2 catalysts exhibited obvious classified action by 89% and 91% yielding amount of benzaldehyde after 4 h for reaction temperature 80 and 90 °C, respectively. The differentiation between them in the catalytic reactivity was depending on the heterogeneity and the effect of the coated TiO2–ZnO nanoparticles on the VOL2 catalytic potential. The kinetic parameter of the productive redox protocols for both catalyst was examined. Additionally, some other cyclic and acyclic alcohols were exhibited the productive redox protocol in the optimum control of both catalysts.

Acyclic Diterpene Phytol from Hemp Seed Oil (Cannabis sativa L.) Exerts Anti-Inflammatory Activity on Primary Human Monocytes-Macrophages.

Seeds from non-drug varieties of hemp (Cannabis sativa L.) have been used for traditional medicine, food, and fiber production. Our study shows that phytol obtained from hemp seed oil (HSO) exerts anti-inflammatory activity in human monocyte-macrophages. Fresh human monocytes and human macrophages derived from circulating monocytes were used to evaluate both plasticity and anti-inflammatory effects of phytol from HSO at 10–100 mM using FACS analysis, ELISA, and RT-qPCR methods. The quantitative study of the acyclic alcohol fraction isolated from HSO shows that phytol is the most abundant component (167.59 ± 1.81 mg/Kg of HSO). Phytol was able to skew monocyte-macrophage plasticity toward the anti-inflammatory non-classical CD14+CD16++ monocyte phenotype and toward macrophage M2 (CD200Rhigh and MRC-1high), as well as to reduce the production of IL-1β, IL-6, and TNF-α, diminishing the inflammatory competence of mature human macrophages after lipopolysaccharide (LPS) treatment. These findings point out for the first time the reprogramming and anti-inflammatory activity of phytol in human monocyte-macrophages. In addition, our study may help to understand the mechanisms by which phytol from HSO contributes to the constant and progressive plasticity of the human monocyte-macrophage linage.

Biomedical Activities of Florasol

Florasol is an acyclic alcohol of diterpene regularly available in certain aromatic plants' essential oils, such as Lantana radula and Cleome serrata. Florasol is a plant phytochemical phytoconstituent which is extensively spread in nature. Florasol is a branched-chain unsaturated alcohol which is present day in all plants in the form of chlorophyll. Cytotoxic, antibiotic chemotherapy, antidiabetic, anti-hyperalgesic, antimutagenic, anti-teratogenic, anticonvulsant, anti-schistosomal, lipid restriction, antimicrobial, antitumor, anti-scratching behavioral effects, antifungal, anti-inflammatory antispasmodic, anxiolytic, hair growth facilitator, antidepressant, and immune adjuvant have been shown evidence to have florasol as well as its derivatives. Recent investigations with florasol (PYT) demonstrated anxiolytic, metabolism-modulating, cytotoxic, antioxidant, autophagy- and apoptosis-inducing, antinociceptive, anti-inflammatory, immune-modulating, and antimicrobial effects. The benefit of florasol in the human body is necessary. In reference to technological bases, patent present a wide range of pharmacological and commercial applications such as cosmetics, hypolipidemic, anxiolytic, and antidepressant. Therefore, it is necessary to explore florasol molecules, which present high pharmacological potential from scientific and technological points of view, in search of transference of technologies to generate economical and industrial growth.

Farnesol-Loaded Nanoliposomes Inhibit Inflammatory Gene Expression in Primary Human Skeletal Myoblasts.

Simple SummaryObesity leads to the accumulation of free fatty acids (FFAs) and inflammation in skeletal muscle, which results in the loss of muscle mass and function. Farnesol is a natural hydrophobic compound from plants with poor bioavailability. We used a liposomal delivery system to direct farnesol into muscle cells and examined its possible beneficial effects on restraining inflammation. Our data strongly suggest that farnesol acts as a potent inhibitor of inflammatory gene expression in human myoblasts.There is a substantial unmet need for the treatment of skeletal muscle mass loss that is associated with aging and obesity-related increases in FFA. Unsaturated FFAs stimulate the inflammatory gene expression in human skeletal myoblasts (SkMs). Farnesol is a hydrophobic acyclic sesquiterpene alcohol with potential anti-inflammatory effects. Here, we created farnesol-loaded small unilamellar (SUVs) or multilamellar lipid-based vesicles (MLVs), and investigated their effects on inflammatory gene expression in primary human skeletal myoblasts. The attachment of SUVs or MLVs to SkMs was tracked using BODIPY, a fluorescent lipid dye. The data showed that farnesol-loaded SUVs reduced FFA-induced IL6 and LIF expression by 77% and 70% in SkMs, respectively. Farnesol-loaded MLVs were less potent in inhibiting FFA-induced IL6 and LIF expression. In all experiments, equal concentrations of free farnesol did not exert significant effects on SkMs. This report suggests that farnesol, if efficiently directed into myoblasts through liposomes, may curb FFA-induced inflammation in human skeletal muscle.

Farnesol Promotes Apoptosis and Inhibits Invasion of Nasopharyngeal Carcinoma Cells

Farnesol—an acyclic sesquiterpene alcohol common to certain plant oils—exerts anti-inflammatory and anticancer effects in a variety of tumor cell lines. Herein, we have examined the roles of farnesol in nasopharyngeal carcinoma cell apoptosis and metastasis. The results show that farnesol significantly reduced cell viability and decreased the number of colonies of nasopharyngeal carcinoma. Farnesol promoted cell apoptosis by downregulating expression of B-cell lymphoma 2 protein and upregulating BCL2-associated X protein, cleaved caspase-3, and cleaved caspase-9. Suppression by farnesol was associated with enhanced expression of E-cadherin, reduced expression of N-cadherin, snail, matrix metalloproteinases-2, and matrix metalloproteinases-9 along with decreased phosphorylation of protein kinase B and mammalian target of rapamycin. In conclusion, farnesol exerts anticancer effect against nasopharyngeal carcinoma through inactivation of phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling.

Geraniol, a natural monoterpene, identifications of cytotoxic and genotoxic effects in vitro

ABSTRACT Geraniol (GER) is an acyclic monoterpene alcohol. This study aimed to investigate the cytotoxic and genotoxic effect of GER in human lymphocytes using chromosomal aberrations (CAs) micronucleus (MN) assays and DNA damaging effect using comet assay in isolated human lymphocytes as well as cytotoxic effect in MCF-7 cells using MTT and Neutral red uptake (NRU) assays. Cells were treated with between 4 and 500 µg/mL of GER. GER significantly reduced the cell viability at 4, 20, 100 and 500 µg/mL at 48 hours in MCF-7 cells. GER also had a cytotoxic effect by lowering the mitotic index at 20–100 μg/mL in human lymphocytes. GER significantly induced the frequency of CAs and CA/cell at both treatments. GER did not significant affect the MN frequency. GER significantly increased the comet tail intensity and moment at 50, 100, and 500 µg/mL. GER exerted cytotoxic and genotoxic effects especially at higher concentrations.

Efficient α-Alkylation of Arylacetonitriles with Secondary Alcohols Catalyzed by a Phosphine-Free Air-Stable Iridium(III) Complex.

A well-defined and readily available air-stable dimeric iridium(III) complex catalyzed α-alkylation of arylacetonitriles using secondary alcohols with the liberation of water as the only byproduct is reported. The α-alkylations were efficiently performed at 120 °C under solvent-free conditions with very low (0.1-0.01 mol %) catalyst loading. Various secondary alcohols including cyclic and acyclic alcohols and a wide variety of arylacetonitriles bearing different functional groups were converted into the corresponding α-alkylated products in good yields. Mechanistic study revealed that the reaction proceeds via alcohol activation by metal-ligand cooperation with the formation of reactive iridium-hydride species.

Cyclic and acyclic alcohols: a structure-activity relationship study correlation between insecticidal activity and chemical structure

The efficiency of essential oil depends upon the chemical nature, composition, and the relative proportion of its functional groups. In some case, individual compounds can exhibit a pertinent effect than do the essential oils. To underline their efficiency according to their chemical structure, five cyclic and acyclic alcohols were tested in vitro for their potential insecticidal and repellent activities against Tribolium castaneum (Herbst). The ability to repel more than 95% was observed in all tested compounds from 15 min to 10 h, except for eugenol that exhibited the weakest effect. Fumigant bioassay showed that the five alcohols applied separately caused significant insect mortality that exceeds 60% at 400 μL/L air. The lowest median lethal dose, LC50 = 18.24 μL/L was observed with citronellol. PCA analysis revealed that the acyclic alcohols showed stronger toxicity compared to the cyclic ones. Moreover, the combined effect of these alcohols was lower than individual ones in all tested combinations. According to the outcome of this study, acyclic alcohols might be more effective in reducing stored grain Tribolium infestation than cyclic ones as a single compound. The knowledge of the degree of efficiency of each chemical group gives the possibility to create artificial combinations of different constituents for the development of more effective eco-friendly control agents.

Синтетические меротерпеноиды на основе терпеновых спиртов: синтез, самосборка и мембранотропные свойства

Currently, targeted drug delivery is of great interest in the field of medicine. The study of compounds capable of permeating cell membranes is a major problem in this area. The synthesis of pharmacologically active compounds includes the formation of structures with various combinations of pharmacophore fragments and properties. Amphiphilic compounds tend to exhibit membranotropic activity. From this point of view, the modification of natural products, especially terpenoids, is of particular interest. Terpenoid structures are used as membrane anchors in the development of modulators for membrane-integrated proteins or structures for creating nanocontainers. In this paper we synthesized a number of water-soluble amphiphilic meroterpenoids containing a charged pyridinium fragment on the basis of acyclic terpene alcohols. Residue of terpene alcohols – geraniol (monoterpenol), farnesol (sesquiterpenol), and phytol (diterpenol) – were used as the hydrophobic part of the amphiphilic structure. Linear acyclic alcohols are commercially available reagents and have a structure similar to that of polyprenols in archaeal lipids, which made it possible to obtain synthetic lipid-like meroterpenoids capable of self-assembly in aqueous solutions. The charged pyridinium fragment, which is included in numerous natural compounds, was of interest as a polar component. This meroterpenoids are synthetic analogs of archaeal lipids. It was shown that the studied meroterpenoids form nanosized aggregates in aqueous solutions by the method of dynamic light scattering and the Doppler microelectrophoresis method. Turbidimetric titration on model dipalmitoylphosphatidylcholine vesicles revealed that the synthesized compounds are embedded into the bilayer membrane without destroying it. Self-assembled aggregates of synthesized compounds in water can find application for drug delivery – in the creation of nanocontainers containing membrane anchors capable of interacting with the outer surface of the cell (lipid membrane).

Anti-inflammatory glycosides from the roots of Paeonia intermedia C. A. Meyer

Three new phenolic glycosides, intermedia A–C (1–3), one new acyclic alcohol glycoside, intermedia D (4), together with 3 known glycosides (5–7), were isolated from the dried roots of Paeonia intermedia C. A. Meyer. Their structures were established by means of extensive spectroscopic analysis (HRESIMS, NMR). Compound 1 have a rare benzo[1,5]dioxepine skeleton. The bioassay results showed that compound 3 exhibited inhibitory activity against proinflammatory cytokines nitric oxide (NO) secretion in LPS-activated RAW264.7 cells with an IC50 value of 85.76 ± 1.36 μM.

Phytol: A review of biomedical activities

Phytol (PYT) is a diterpene member of the long-chain unsaturated acyclic alcohols. PYT and some of its derivatives, including phytanic acid (PA), exert a wide range of biological effects. PYT is a valuable essential oil (EO) used as a fragrance and a potential candidate for a broad range of applications in the pharmaceutical and biotechnological industry. There is ample evidence that PA may play a crucial role in the development of pathophysiological states. Focusing on PYT and some of its most relevant derivatives, here we present a systematic review of reported biological activities, along with their underlying mechanism of action. Recent investigations with PYT demonstrated anxiolytic, metabolism-modulating, cytotoxic, antioxidant, autophagy- and apoptosis-inducing, antinociceptive, anti-inflammatory, immune-modulating, and antimicrobial effects. PPARs- and NF-κB-mediated activities are also discussed as mechanisms responsible for some of the bioactivities of PYT. The overall goal of this review is to discuss recent findings pertaining to PYT biological activities and its possible applications.

Fluorescent cyclodextrins as chemosensors for the detection of cyclic and acyclic alcohols

Molecular sensing abilities and selectivities of a “turn-on” chemosensor, NBDamine-appended α-cyclodextrin (NC0αCD), were studied for cyclic alcohols and acyclic alcohols. This chemosensor is more sensitive to cyclic alcohols than acyclic alcohols, although its binding affinity is stronger for acyclic alcohols than cyclic alcohols.

Reaction of 2-trifluoroacetyl-1,8-Bis(dimethylamino)naphthalene with strong organic bases: Deprotonation of 1-NMe2 group resulting in the formation of Benzo[g]indole derivatives versus nucleophilic addition to C[dbnd]O group

A novel approach to pyrrole ring closure in 2-trifluoroacetyl- and 2-ethoxycarbonyl-1,8-bis(dimethylamino)naphthalenes via treatment with 2-lithium-1,8-bis(dimethylamino)naphthalene producing the corresponding benzo[g]indole derivatives, was examined with different alkyl- and aryllithium compounds as well as with LDA. It was found that the highest yields of benzo[g]indoles (up to 70%) are obtained with aryllithium reagents when they contain NMe2 group in ortho-position to the carbanionic centre. In all other cases the formation of acyclic alcohol arising from ordinary intermolecular addition of the carbanion to the CO group strongly prevails. The dramatic facilitation of deprotonation of the N-Me group in substrate followed by pyrrolic cyclization in the case of 2-lithium-N,N-dimethylanilines was explained through a specific structure of the reaction transition state.

Coupling gene regulatory patterns to bioprocess conditions to optimize synthetic metabolic modules for improved sesquiterpene production in yeast

BackgroundAssembly of heterologous metabolic pathways is commonly required to generate microbial cell factories for industrial production of both commodity chemicals (including biofuels) and high-value chemicals. Promoter-mediated transcriptional regulation coordinates the expression of the individual components of these heterologous pathways. Expression patterns vary during culture as conditions change, and this can influence yeast physiology and productivity in both positive and negative ways. Well-characterized strategies are required for matching transcriptional regulation with desired output across changing culture conditions.ResultsHere, constitutive and inducible regulatory mechanisms were examined to optimize synthetic isoprenoid metabolic pathway modules for production of trans-nerolidol, an acyclic sesquiterpene alcohol, in yeast. The choice of regulatory system significantly affected physiological features (growth and productivity) over batch cultivation. Use of constitutive promoters resulted in poor growth during the exponential phase. Delaying expression of the assembled metabolic modules using the copper-inducible CUP1 promoter resulted in a 1.6-fold increase in the exponential-phase growth rate and a twofold increase in productivity in the post-exponential phase. However, repeated use of the CUP1 promoter in multiple expression cassettes resulted in genetic instability. A diauxie-inducible expression system, based on an engineered GAL regulatory circuit and a set of four different GAL promoters, was characterized and employed to assemble nerolidol synthetic metabolic modules. Nerolidol production was further improved by 60% to 392 mg L−1 using this approach. Various carbon source systems were investigated in batch/fed-batch cultivation to regulate induction through the GAL system; final nerolidol titres of 4–5.5 g L−1 were achieved, depending on the conditions.ConclusionDirect comparison of different transcriptional regulatory mechanisms clearly demonstrated that coupling the output strength to the fermentation stage is important to optimize the growth fitness and overall productivities of engineered cells in industrially relevant processes. Applying different well-characterized promoters with the same induction behaviour mitigates against the risks of homologous sequence-mediated genetic instability. Using these approaches, we significantly improved sesquiterpene production in yeast.