How Dose Flexible Cis-Octahydropentalene Carbonic Backbone, Help Populate A Single Bioactive Conformer in Chondrosterin J

Sahar Sakhaee1, Saghar Sakhaee2, Mohammad Hossein Sakhaee3, Akbar Mobaraki4, Ahmad Takallou5, Nader Sakhaee6* 1Islamic Azad University, Mashhad Branch 2Medical University of Shahrood, Shahrood, Iran 3Mashhad University of Medical Sciences, Mashhad, Iran 4Department of Chemistry, Tarbiat Modarres University, P.O. Box. 14115-175, Tehran, Iran 5Department of Chemistry, Kharazmi University, Tehran, Iran 6*Department of Mathematics and Natural Sciences, Harris-Stowe State University & Department of Chemistry, Southern Illinois University, USA

certain bioactive folded conformers. And though impossible it may seem to select among a myriad of folding patterns nature has used up enormous geologic time to its benefit to accomplish this. The first pseudo rotational model for cyclopentane was introduced by Lipnick et al. [1]. They suggested a wheel model of a of up to 20 conformers, put in a wheel setting [2,3] to illustrate cyclopentane conformational mobility. Further attempts [4][5][6][7][8][9][10][11] to classify these conformers mostly proved unsuccessful [12][13][14]. The concept of a spherical conformational landscape was introduced back (Figure 1) in 2016, to cyclopentane and some of its derivatives which helped fully explain their fluxional nature. A basic spherical conformational landscape was also presented for cis-octahydropentalene. Here it's been tried to analyze the conformational preferences of Cis-Octahydropentalene in a way to justify the conformational preferences of natural products containing this fascinating molecule. Our results with Chondrosterin and initial results with other natural products are rather a strong back up for the grand theory that nature exploits special features in certain cyclic carbonic scaffolds to achieve desired boioactivity.

Methods
To study conformational forms in parent Cis-Octahydropentalenes as well as Chondrosterin, most local density functional methods, slightly overestimate barriers due to their inability to account for van der Waals attractions in twist conformations [15,16].
However, density functional methods like xb97xd, in particular yield results similar if not close to those obtained via correlational methods like MP2. The ωb97xd (used here) can reliably result in accurate van der Waals modifications. The geometries computations were done at ωb97xd/6-311+G(d) level [17][18][19], using Gaussian g09 package [20]. Larger basis sets like 6-311+G(d,p) proved small to no better accuracy.

Results and Discussion
In fused five membered rings like octahydropentalenes, cisoctahydropentalene is not only the most stable form but is also a partially flexible molecule. There are 13 double bent forms (cEE),  (Figure 2). Energies for all of these conformers are given in (Table 1). These double bent forms not only are the most stable have the most symmetric conformer class with C2 symmetric forms. Twist conformers lie between 4.5 and 6kcal/mol higher than the double bent while cHCHC1 is 2.5kcal/mol higher, and the other double half-chair is about 6.8kcal/mol higher than the reference cEE3 conformer.  The main role is played by conformer cEE9/cEE6 and cEE3, with the formers acting as a dynamic rapped bioactive part. This shows that most mobile atoms are the ones farthest from the junction carbons. The cEE2 and cEE5 are the only isolated double envelopes, which are only accessible via cEE6 and EE9 respectively.
Both of which have been identified here in Chondrosterin to act as conformational trap sites. They both have their out of plane carbons as the junction carbons, which serve as a lock to any plausible ring flipping. Chondrosterin have also been reported to have major conformer cEE9 and cEE3. Populated the same major conformer a dime has also been identified via crystallographic studies ( Figure   3). Cis-octahydropentalenes are both more stable and of more frequent occurrences in nature compared to their trans isomers.
Natural cedrol and Cederenes are the essential components in cedar oils of most coniferous trees [22]. Aburatsubo lactam is a novel inhibitor of superoxide anions isolated from a marine organism [11].

Conclusion
In conclusion, we have suggested a reasonable Conformational landscape for cis-Octaheydropentalene. The pattern successfully explains the bioactive conformation in Chondrosterin, a marine natural product with potent bioactivity. Seemingly contradictory properties of Chondrosterin's major conformer cEE9, as both a flexible and yet highly populated conformer, strongly suggests, natures choice to select cis-Octaheydropentalene frameworks in many natural products. Analysis like these are not only illustrative on how nature can use certain scaffolds to achieve bioactivity at its highest potency but would fuel biomedical research in the drug design area.