Current advances in gibberellic acid (GA3) production, patented technologies and potential applications.

MAIN CONCLUSION: Gibberellic acid is a plant growth hormone that promotes cell expansion and division. Studies have aimed at optimizing and reducing production costs, which could make its application economically viable for different cultivars. Gibberellins consist of a large family of plant growth hormones discovered in the 1930s, which are synthesized via the terpenes route from the geranylgeranyl diphosphate and feature a basic structure formed by an ent-gibberellane tetracyclic skeleton. Among them, only four have biological activity, including gibberellic acid (GA3), which acts as a natural plant growth regulator, especially for stem elongation, seed germination, and increased fruit size. It can be obtained from plants, fungi, and bacteria. There are also some reports about microalgae GA3 producers. Fungi, especially Gibberella fujikuroi, are preferred for GA3 production via submerged fermentation or solid-state fermentation. Many factors may affect its production, some of which are related to the control and scale-up of fermentation parameters. Different GA3 products are available on the market. They can be found in liquid or solid formulations containing only GA3 or a mixture of other biological active gibberellins, which can be applied on a wide variety of cultivars, including crops and fruits. However, the product's cost still limits its large and continuous application. New low-cost and efficient GA3 production alternatives are surely welcome. This review deals with the latest scientific and technological advances on production, recovery, formulation, and applications of this important plant growth hormone.

Tailoring of a Potential Nanoformulated Form of Gibberellic Acid: Synthesis, Characterization, and Field Applications on Vegetation and Flowering.

Nanoformulation of agrochemicals has become a potential choice to improve the physicochemical properties, enhance the utilization efficiency, and reduce the side effects and ecotoxicity of many hazardous chemicals. Here, we tailored a new formulation platform for gibberellic acid (GA) using the layered double hydroxides (LDH) as a potential carrier. Typically, we synthesized, characterized, and potentially applied the newly nanoformulated form of GA on the quantity and quality properties of Dendranthema grandiflorum cultivar. We also evaluated the synergetic effect of the carrier LDH on the release behavior of GA, showing a remarkable impact on the utilization efficiency of GA. The nanohybrid structure of GA also showed an enhanced thermal stability and safe preservation for the incorporated moieties. Taking into account the hazardous effect of free GA on the environment and human health, the hybrid technique of GA is one of the best choices among all of the studied protocols.

Synthesis and anti-proliferative activity of allogibberic acid derivatives containing 1,2,3-triazole pharmacophore.

Sixty novel allogibberic acid derivatives containing 1,2,3-triazole pharmacophore were designed and synthesized. The key chemical processes include aromatization of the A ring in gibberellins, formation of allogibberic azides and its copper mediated Huisgen 1,3-dipolar cycloaddition with alkynes. A number of hybrids containing α,ß-unsaturated ketone moiety exhibited excellent in vitro cytotoxic activities. Some of the hybrids were more selective to MCF-7 and SW480 cell lines with IC50 values at least 8-fold more cytotoxic than cisplatin (DDP). The most potent compounds C43 and C45 are more cytotoxic than cisplatin (DDP) against all tested five tumor cell lines, with IC50 values of 0.25-1.72 µM. Mechanism of action studies indicated that allogibberic-triazole derivative C45 could induce the S phase cell cycle arrest and apoptosis in SMMC-7721 cell lines.

Syntheses of Gibberellins A15 and A24, the Key Metabolites in Gibberellin Biosynthesis.

Gibberellins (GAs) are essential phytohormones involved in numerous aspects of plant growth and development. Notably, the biochemistry and genetics of GA biosynthesis, which is associated with their endogenous regulation, have been largely resolved; however, a crucial unsolved question remains: the precise mechanism of the stepwise oxidation and subsequent removal of C-20 from C20 precursors, leading to bioactive C19 gibberellins, is still unresolved. To satisfy numerous requests from biologists, practical preparations of certain GAs that were isolated in miniscule quantities are highly demanded. Herein, we report the first practical syntheses of GA15 and GA24, the key C20 metabolites in gibberellin biosynthesis, from commercially available GA3. The protocols are robust and offer the capacity to produce GA24 and GA15 under gram scales in high overall yields and thus aid in further biological and related studies.

Chemical screening and development of novel gibberellin mimics.

Gibberellin (GA) plays versatile roles in the regulation of plant growth and development and therefore is widely used as a regulator in agriculture. We performed a chemical library screening and identified a chemical, named 67D, as a stimulator of seed germination that was suppressed by paclobutrazol (PAC), a GA biosynthesis inhibitor. In vitro binding assays indicated that 67D binds to the GID1 receptor. Further studies on the structure-activity relationship identified a chemical, named chemical 6, that strongly promoted seed germination suppressed by PAC. Chemical 6 was further confirmed to promote the degradation of RGA (for repressor of ga1-3), a DELLA protein, and suppress the expression levels of GA3ox1 in the same manner as GA does. 67D and its analogs are supposed to be agonists of GID1 and are expected to be utilized in agriculture and basic research as an alternative to GA.

Synthesis of Gibberellic Acid Derivatives and Their Effects on Plant Growth.

A series of novel C-3-OH substituted gibberellin derivatives bearing an amide group were designed and synthesized from the natural product gibberellic acid (GA3). Their activities on the plant growth regulation of rice and Arabidopsis were evaluated in vivo. Among these compounds, 10d and 10f exhibited appreciable inhibitory activities on rice (48.6% at 100 µmol/L) and Arabidopsis (41.4% at 100 µmol/L), respectively. These results provide new insights into the design and synthesis of potential plant growth regulators.

Synthesis of gibberellin derivatives with anti-tumor bioactivities.

A series of gibberellin based molecules were designed and synthesized. Gibberellin derivatives bearing two alpha,beta-unsaturated ketone units showed strong anticancer activities in MTT assay towards a number of human cancer cell lines including HT29, A549, HepG2 and MKN28. The most potent gibberellin derivative (compound 10, IC(50)=2.9 microM against HT29) inhibited completely the topoisomerase I activity at 8 microg/mL level.

Synthesis and bioactivity of the gibberellin, 18-hydroxy-GA1 (GA132).

As part of a study to confirm putative structural assignments to new gibberellins and to furnish sufficient quantities for biological investigations, a twenty step synthesis of 18-hydroxy GA1 from gibberellic acid (GA3) is described, allowing the confirmation of structure for a new gibberellin, GA132, that occurs in developing grains of barley (Hordeum vulgare). The early part of the sequence involved cleavage of the C(3)-C(4) bond in the A-ring of a 3-oxo intermediate. The ring was then reformed as part of a "domino" process involving the conjugate addition of alkoxide to an alpha-methylene lactone moiety followed by an intramolecular aldol reaction. The bioactivities of the new GA, and its 18-hydroxy-GA4 relative, have been confirmed in dwarf barley growth and alpha-amylase induction assays.

Synthesis and confirmation of structure for the gibberellin GA131 (18-hydroxy-GA4).

A general method for the hydroxylation of the 18-methyl group in gibberellins has been developed, as demonstrated by the successful synthesis of 18-hydroxy GA(4) (GA(131)) by means of a tandem process involving the conjugate addition of alkoxides to the alpha-methylene lactone moiety of a ring A-seco-gibberellin followed by an intramolecular aldol reaction.

Synthesis of gibberellin GA6 and its role in flowering of Lolium temulentum.

The induction of flowering by one long day (LD) in the grass Lolium temulentum is most closely mimicked by application of the gibberellins (GAs) GA(5) or GA(6), both of which occur naturally. These gibberellins promote floral development but have little effect on stem elongation. Endogenous GA(5) and GA(6) contents in the shoot apex double on the day after the LD and, for GA(5) (and we presume for GA(6) as well) reach a concentration known to be inductive for the excised shoot apex in vitro. They are, therefore, strong candidates as LD floral stimuli in this grass. The synthesis of GA(6) and an examination of its florigenic properties in L. temulentum are described.

Synthesis and confirmation of structure for a new gibberellin, 2 beta-hydroxy-GA12 (GA110), from spinach and oil palm.

The identity of a new gibberellin (GA) in spinach and oil palm sap has been confirmed as 2 beta-hydroxy-GA12 (GA110) by comparisons of GC-mass spectral data obtained for the trimethylsilyl ether methyl ester derivatives with those of a synthetic sample prepared by means of a 24 step sequence from gibberellic acid; 2 beta-hydroxy-GA24 was also prepared. Experimental details for the latter part of the syntheses are described.

Preparation of monoclonal antibodies specific for methyl esters of gibberellins A7 and A4.

According to the heterogeneity of the immunogen of GA3-3-O-HSA, which contained other components such as GA3-7-CONH-HSA, two kinds of monoclonal antibodies (MAbs) against different antigen determinants of GA3 were prepared in a single process using a two-step screening assay for hybridomas. The results from a cross-reactivity experiment showed that MAb BG2 was specific for GA7/4 methyl esters (GA7/4me) with high affinity. Its affinity for GA7me was over 100 and 200 times higher than for GA3me and GA1me, respectively. Methylation of the 7-oic acid significantly increased the binding of MAb BG2 with GAs. On the contrary, the absence of a double bond or 3beta-OH in ring A and the breakdown of 19,10-gamma-lactone as well as the presence of 13-OH in ring D greatly reduced the binding of MAb BG2 with GAs. This antibody with high specificity can be used effectively to quantify and localize the main active GA7 and GA4 from the early non-hydroxylation pathway of GAs metabolism. Using this antibody, enzyme immunoassays with high sensitivity were developed which displayed linear ranges from 1.0 x 10(-14) to 1.0 x 10(-12) mol for GA4me and from 2.0 x 10(-15) to 2.0 x 10(-13) mol for GA7me.