Unprecedented sesterterpenoids, orientanoids A-C: discovery, bioinspired total synthesis and antitumor immunity.

Sesterterpenoids are a very rare class of important natural products. Three new skeletal spiro sesterterpenoids, named orientanoids A-C (1-3), were isolated from Hedyosmum orientale. Their structures were determined by a combination of spectroscopic data, X-ray crystallography, and total synthesis. To obtain adequate materials for biological research, the bioinspired total syntheses of 1-3 were effectively achieved in 7-8 steps in overall yields of 2.3-6.4% from the commercially available santonin without using any protecting groups. In addition, this work also revised the stereochemistry of hedyosumins B (6) and C (10) as 11R-configuration. Tumor-associated macrophages (TAMs) have emerged as important therapeutic targets in cancer therapy. The in-depth biological evaluation revealed that these sesterterpenoids antagonized the protumoral and immunosuppressive functional phenotype of macrophages in vitro. Among them, the most potent and major compound 1 inhibited protumoral M2-like macrophages and activated cytotoxic CD8+ T cells, and consequently inhibited tumor growth in vivo.

Allylic hydroxylation of enones useful for the functionalization of relevant drugs and natural products.

Enones are privileged structural motifs in bioactive natural products and pharmaceuticals, but the γ-hydroxylation of enones is challenging. Here we show a mild and efficient method for the direct C(sp3)-H hydroxylation of enones via visible-light-induced hydrogen-atom transfer (HAT), which facilitates γ-hydroxylation of primary, secondary, and tertiary C-H bonds of different enones without involving metal and peroxide. The mechanism study shows that Na2-eosin Y serves as both the photocatalyst and the source of catalytic bromine radical species in the HAT-based catalytic cycle, and finally sacrifices itself completely by oxidative degradation to produce bromine radical and a major product phthalic anhydride in an environmentally friendly way. This scalable method was demonstrated by plenty of substrates (41 examples) including 10 clinical drugs and 15 natural products to be useful for the late-stage functionalization of enone-containing compounds, and, in particular, has potential application in industry for large-scale production.

Baccaramiones A-D, Four Highly Oxygenated and Rearranged Trinorditerpenoids from Baccaurea ramiflora.

Baccaramiones A-D (1-4), four highly oxygenated and rearranged trinorditerpenoids, were isolated from Baccaurea ramiflora. Compound 1 is a 1(10 → 5)-abeo-15,16,17-trinor-ent-abietane featuring a unique 5/6/6 spirocyclic scaffold, and 2-4 are the first example of a novel 20(10 → 5)-abeo-15,16,17-trinor-ent-abietane skeleton. Their structures were established by spectroscopic analysis, X-ray crystallography, and electronic circular dichroism calculations. A plausible biosynthetic pathway for 1-4 was proposed. Interestingly, compounds 3 and 4 exhibited significant immunosuppressive activities against concanavalin A-induced T cell proliferation and lipopolysaccharide-induced B cell proliferation in vitro.

Discovery of four modified classes of triterpenoids delineated a metabolic cascade: compound characterization and biomimetic synthesis.

Chemical studies on Dichapetalum gelonioides have afforded 18 highly modified complex triterpenoids belonging to four compound classes as defined by the newly adapted functional motifs associated with the A ring of the molecules. Their structures were determined by solid data acquired by diverse methods. The biosynthetic pathway for the four compound classes was rationalized via cascade modifications involving diverse chemical events. The subsequent biomimetic syntheses afforded all the desired products, including compounds 16 and 19 that were not obtained in our purification, which validated the proposed biosynthetic pathway. Besides, some compounds exhibited strong cytotoxic activities, especially 2 and 4 showed nanomolar potency against the NAMALWA tumor cell line, and a gross structure-activity relationship (SAR) of these compounds against the tested tumor cell lines was delineated.

Cephalodiones A-D: Compound Characterization and Semisynthesis by [6+6] Cycloaddition.

Cephalodiones A-D (1-4), the first example of C19 -norditerpenoid dimers, were isolated and fully characterized from a Cephalotaxus plant. These new skeletal natural products shared a unique tricyclo[6.4.1.12,7 ]tetradeca-3,5,9,11-tetraene-13,14-dione core that was capped in both ends with rigid multicyclic ring systems either C2 -symmetrically or asymmetrically. Compounds 1-4 were proposed to be biosynthetically produced by the [6+6]-cycloaddition of two identical C19 -norditerpenoid troponoids, which was validated by the semisyntheses of dimers 2-4. Moreover, some compounds showed significant inhibition on Th17 cell differentiation.

[Cyclophosphamide-induced rat ovarian damage and expression of gonadotropin-releasing hormone receptor in the damaged ovaries].

OBJECTIVE: To investigate ovarian follicular damage induced by chemotherapeutic agents and gonadotropin- releasing hormone receptor (GnRHR) expression in the damaged ovaries in rats. METHODS: Two groups of adult SD rats were subjected to intraperitoneal injection of a single-dose cyclophosphamide and saline, respectively, and 8 weeks later, the ovaries were taken for observing the ovarian damages. The distribution of GnRHR was detected with immunohistochemistry, and RT-PCR was used to determine the expression of GnRHR mRNA in the rat ovaries. RESULTS: Massive primordial follicular loss occurred in the ovaries of rats exposed to cyclophosphamide with also evident stromal ovarian blood vessel damages and focal fibrosis. Both the protein and mRNA expressions of GnRHR were detected in normal rat ovaries, but in rats exposed to cyclophosphamide, the expressions were significantly lowered in the ovaries (P<0.05). CONCLUSION: Low-level GnRHR expressions in the ovaries of rats with cyclophosphamide exposure suggest microenvironment disturbances in the damaged rat ovaries in advanced stage of chemotherapy.

[Effects of gonadotropin releasing hormone analogues on chemotherapy-induced ovarian function damage in rats].

OBJECTIVE: To investigate the effects of gonadotropin releasing hormone agonist (GnRH-a) and antagonist (GnRH-ant) on cyclophosphamide (CTX)-induced ovarian damage in rats. METHODS: Seventy-two Sprague-Dawley female rats were divided randomly into six groups, which received normal saline (NS), CTX, GnRH-a + NS, GnRH-a + CTX, GnRH-ant + NS, and GnRH-ant + CTX respectively. Levels of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E(2)) were measured successively by the enzyme-linked immunosorbent assay method, and half of the rats were killed in the first week and between the fourth and the fifth week after stop of medication, respectively to compare the weight of the ovaries and the number of the primordial follicles and the growth follicles. RESULTS: (1) Throughout experiment, the serum levels of FSH, LH and E(2) of the control group fluctuated slightly, while those in the CTX group kept rising. During medication treatment, compared with the control group [(118 +/- 16) microg/L, (350 +/- 35) microg/L] and the CTX group [(113 +/- 15) microg/L, (289 +/- 42) microg/L], the concentrations of LH [(42 +/- 8) - (47 +/- 7) microg/L, (31 +/- 5) - (36 +/- 7) microg/L] and FSH [(124 +/- 45) - (136 +/- 32) microg/L, (178 +/- 54) - (198 +/- 27) microg/L] in the GnRH-a groups and the GnRH-ant groups were maintained at low levels significantly and the levels of LH in the GnRH-ant groups were significantly lower than that in the GnRH-a groups, but the levels of FSH in the GnRH-ant groups were significantly higher than that in the GnRH-a groups (P < 0.05); and extremely different from the GnRH-a groups [(0.98 +/- 0.18) - (1.46 +/- 0.22) ng/L], the level of E(2) of the GnRH-ant groups [(3.58 +/- 0.43) - (3.98 +/- 0.74) ng/L] did not significantly decrease (P < 0.01). After stop of therapy, the concentrations of LH, FSH and E(2) in the GnRH-a groups and the GnRH-ant + NS group rose gradually and were similar to the levels of the control group (P > 0.05), but the levels of FSH, LH and E(2) of the GnRH-ant + CTX group rose obviously and were similar to the levels of the CTX group, especially the FSH , and the levels of LH and FSH of the GnRH-ant + CTX group [(156 +/- 12) microg/L, (520 +/- 44) microg/L] and the CTX group [(178 +/- 18) microg/L, (546 +/- 36) microg/L] were significantly higher than that of the other four groups [(121 +/- 15) - (132 +/- 13) microg/L, (335 +/- 35) - (359 +/- 26) microg/L] at the 4(th) - 5(th) week after stop of treatment (P < 0.05). (2) At the 1(st) week after stopping therapy, the GnRH-a + NS group [(12 +/- 5) mg/100 g]and the GnRH-a + CTX group [(18 +/- 8) mg/100 g] had the lowest weight of ovaries which was significantly different from the other groups [(30 +/- 9) - (37 +/- 8) mg/100 g, P < 0.05]. At the 4(th) - 5(th) week after stopping therapy, the GnRH-ant + CTX group [(22 +/- 6) mg/100 g] and the CTX group [(20 +/- 4) mg/100 g] had the lowest weight of ovaries which were significantly different from the other groups [(29 +/- 5) - (31 +/- 9) mg/100 g, P < 0.05]. (3) At the 1(st) week after stopping therapy, there were the largest number of primordial follicles [(824 +/- 45), (689 +/- 39)] and the lowest number of growth follicles [(15 +/- 1), (21 +/- 3)] in the GnRH-a + NS group and the GnRH-a + CTX group, but there were the lowest number of primordial follicles [(255 +/- 24), (343 +/- 29)] and the largest number of growth follicles [(110 +/- 21), (87 +/- 17)] in the GnRH-ant + CTX group and the CTX group. At the 4(th) - 5(th) week after stopping therapy, the number of growth follicles in the GnRH-a + NS group (58 +/- 11) and the GnRH-a + CTX group (56 +/- 16) recovered to almost the level of the control group (57 +/- 9, P > 0.05), but the number of all kinds of follicles declined significantly in the GnRH-ant + CTX group [(195 +/- 15), (36 +/- 12)] and the CTX group [(212 +/- 11), (36 +/- 9)] compared to the other four groups [(302 +/- 15) - (690 +/- 43), (44 +/- 12) - (58 +/- 11), P < 0.05]. CONCLUSION: In rat model, GnRH-a prevents the ovarian function damage induced by CTX, but GnRH-ant does not show similar protective effect.