1.Synthesis and applications of secondary amine derivatives of (+)-dehydroabietylamine in chiral molecular recognition.
Laaksonen T1, Heikkinen S, Wähälä K. Org Biomol Chem. 2015 Nov 14;13(42):10548-55. doi: 10.1039/c5ob01667c. Epub 2015 Sep 4.
(+)-Dehydroabietylamine (1a), the novel derivatives (2a-6a) and their NTf2 salts (1b-6b) were tested as chiral NMR solvating agents for the resolution of enantiomers of the model compound Mosher's acid (7) and its n-Bu4N salt (8). Best enantiomeric discrimination of 7 was obtained using bisdehydroabietylamino-N(1),N(2)-ethane-1,2-diamine (6a), and of 8 using N-(dehydroabietyl)-2-(dehydroabietylamino)ethanaminium bis((trifluoromethyl)-sulfonyl)-amide (6b). For the maximal resolution of enantiomers of 8, 1.0 eq. of 6b were needed. However, 0.5 eq. of 6a sufficed for the maximal resolution of enantiomers of 7. Enantiomeric excess studies were successfully conducted using 6a and 6b. The capability of 6a and 6b to recognize the enantiomers of various α-substituted carboxylic acids and their n-Bu4N salts were examined. Best resolutions were observed for aliphatic and aromatic carboxylic acids bearing an electronegative α-substituent. Now the ee studies on such non-aromatic carboxylic acids are also feasible.
2.(+)-Dehydroabietylamine derivatives target triple-negative breast cancer.
Ling T1, Tran M1, González MA2, Gautam LN1, Connelly M1, Wood RK3, Fatima I3, Miranda-Carboni G3, Rivas F4. Eur J Med Chem. 2015 Sep 18;102:9-13. doi: 10.1016/j.ejmech.2015.07.034. Epub 2015 Jul 23.
Breast cancer remains the leading cause of cancer-related death among women. The invasive triple-negative subtype is unresponsive to estrogen therapy, and few effective treatments are available. In search of new chemical scaffolds to target this disease, we conducted a phenotypic screen against the human breast carcinoma cell lines MDA-MB-231, MA11, and MCF-7 using terrestrial natural products. Natural products that preferentially inhibited proliferation of triple-negative MDA-MB-231 cells over estrogen receptor-positive cells were further studied; herein we focused on the abietanes. The activity of the abietane carnosol prompted us to generate a focus library from the readily available (+)-dehydroabietylamine. The lead compound 61 displayed a promising EC50 of 9.0 μM against MDA-MB-231 and our mechanistic studies indicate it induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of PARP. Here we describe our current progress towards this promising therapeutic candidate.
3.Anti-herpetic and anti-dengue activity of abietane ferruginol analogues synthesized from (+)-dehydroabietylamine.
Roa-Linares VC1, Brand YM1, Agudelo-Gomez LS2, Tangarife-Castaño V2, Betancur-Galvis LA1, Gallego-Gomez JC3, González MA4. Eur J Med Chem. 2016 Jan 27;108:79-88. doi: 10.1016/j.ejmech.2015.11.009. Epub 2015 Nov 11.
The abietane-type diterpenoid (+)-ferruginol (1), a bioactive compound isolated from several plants, has attracted much attention as consequence of its pharmacological properties, which includes antibacterial, antifungal, antimicrobial, cardioprotective, anti-oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and antitumor actions. In this study, we report on the antiviral evaluation of ferruginol (1) and several analogues synthesized from commercial (+)-dehydroabietylamine. Thus, the activity against Human Herpesvirus type 1, Human Herpesvirus type 2 and Dengue Virus type 2, was studied. Two ferruginol analogues showed high antiviral selectivity index and reduced viral plaque-size in post-infection stages against both Herpes and Dengue viruses. A promising lead, compound 8, was ten-fold more potent (EC50 = 1.4 μM) than the control ribavirin against Dengue Virus type 2. Our findings suggest that the 12-hydroxyabieta-8,11,13-triene skeleton, which is characteristic of the diterpenoid ferruginol (1), is an interesting molecular scaffold for development of novel antivirals.
4.A non-cytotoxic N-dehydroabietylamine derivative with potent antimalarial activity.
Sadashiva MP1, Gowda R2, Wu X3, Inamdar GS2, Kuzu OF2, Rangappa KS4, Robertson GP2, Gowda DC5. Exp Parasitol. 2015 Aug;155:68-73. doi: 10.1016/j.exppara.2015.05.002. Epub 2015 May 14.
Malaria caused by the Plasmodium parasites continues to be an enormous global health problem owing to wide spread drug resistance of parasites to many of the available antimalarial drugs. Therefore, development of new classes of antimalarial agents is essential to effectively treat malaria. In this study, the efficacy of naturally occurring diterpenoids, dehydroabietylamine and abietic acid, and their synthetic derivatives was assessed for antimalarial activity. Dehydroabietylamine and its N-trifluoroacetyl, N-tribromoacetyl, N-benzoyl, and N-benzyl derivatives showed excellent activity against P. falciparum parasites with IC50 values of 0.36 to 2.6 µM. Interestingly, N-dehydroabietylbenzamide showed potent antimalarial activity (IC50 0.36), and negligible cytotoxicity (IC50 >100 µM) to mammalian cells; thus, this compound can be an important antimalarial drug. In contrast, abietic acid was only marginally effective, exhibiting an IC50 value of ~82 µM.
